Acute myeloid leukemia pathophysiology: Difference between revisions

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{{Acute myeloid leukemia}}
{{Acute myeloid leukemia}}


{{CMG}}; {{AE}} {{HK}} {{RT}} {{CLG}}
{{CMG}}; {{AE}} {{HK}}, {{RT}}, {{CLG}}, {{shyam}}; {{GRR}} {{Nat}}


==Overview==
==Overview==
Acute myeloid leukemia arises from [[myeloblasts]], which are hematologic white cells that are normally involved in [[hematopoiesis]]. Genetic translocations involved in the pathogenesis of acute myeloid leukemia include translocations between chromosome 8 and 21 t(8;21) and translocations between chromosome 15 and 17 t(15;17). Inversions in the chromosomal translocations in chromosome 16 inv(16) are also involved in the pathogenesis of acute myeloid leukemia.
Normal hematopoiesis involves the production of blood cells, and this normal physiologic process is dysregulated in acute myeloid leukemia. The pathophysiology of acute myeloid leukemia involves multiple mechanisms, including altered signal transduction and autonomous proliferation, [[differentiation]] blockade, evasion of apoptosis, and self-renewal. The pathophysiology of [[acute promyelocytic leukemia]] is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene production causes a differentiation block in myeloid cells. There are multiple different binding partners for the ''RARA'' gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.


==Pathophysiology==
==Pathophysiology==
* The malignant cell in acute myeloid leukemia is the [[myeloblast]]. In normal [[haematopoiesis|hematopoiesis]], the myeloblast is an immature precursor of [[myeloid]] white blood cells; a normal myeloblast will gradually mature into a mature white blood cell. However, in acute myeloid leukemia a single myeloblast accumulates genetic changes which "freeze" the cell in its immature state and prevent [[cellular differentiation|differentiation]].<ref>Fialkow PJ: Clonal origin of human tumors. ''Biochim Biophys Acta'' 1976;458:283–321. PMID 1067873 </ref> Such a mutation alone does not cause leukemia; however, when such a "differentiation arrest" is [[Knudson hypothesis|combined with other mutations]] which disrupt genes controlling [[cell growth|proliferation]], the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of acute myeloid leukemia.<ref>Fialkow PJ, Janssen JW, Bartram CR: Clonal remissions in acute nonlymphocytic leukemia: Evidence for a multistep pathogenesis of the malignancy. ''Blood'' 1991;77:1415–1517. PMID 2009365</ref>
In order to understand the pathophysiology of acute myeloid leukemia, it is important to understand normal physiology of [[hematopoiesis]] or blood cell production.
 
===Normal Hematopoiesis===
*[[Hematopoiesis]] is defined as the production of blood cells.
*This process is typically tightly-regulated under physiological conditions via a number of lineage-specific growth factors and lineage-specific growth signaling pathways.
*The differentiation of [[myeloid cells|myeloid stem cells]] into mature myelocytes is controlled by lineage-specific [[transcription factors]] that regulate the expression of lineage-specific [[genes]].
*In normal [[haematopoiesis|hematopoiesis]], the myeloblast is an immature precursor of [[myeloid]] white blood cells.
*A normal myeloblast will gradually mature into a mature [[white blood cell]].
*Normal hematopoiesis is dependent upon specific [[growth factor receptor|growth factor receptors]].
*The two key [[growth factor receptor|growth factor receptors]] involved are as following:
**[[Growth factor receptor|Growth factor receptors]] with intrinsic [[tyrosine kinase]] activity:
***These are expressed on [[CD34|CD34+]] [[hematopoietic]] progenitor [[cells]].
***Examples include receptors for the [[platelet-derived growth factor|platelet-derived growth factors]] ([[platelet-derived growth factor|PDGFs]]), PDGFR A and B, the receptor for [[macrophage colony-stimulating factor|macrophage colony stimulating factor]] ([[macrophage colony-stimulating factor|M-CSF]]), FMS-like tyrosine kinase receptor (FLT3R), and the receptors for Kit ligand (stem cell factor)<ref name="pmid14977821">{{cite journal |vauthors=Müller-Tidow C, Schwäble J, Steffen B, Tidow N, Brandt B, Becker K, Schulze-Bahr E, Halfter H, Vogt U, Metzger R, Schneider PM, Büchner T, Brandts C, Berdel WE, Serve H |title=High-throughput analysis of genome-wide receptor tyrosine kinase expression in human cancers identifies potential novel drug targets |journal=Clin. Cancer Res. |volume=10 |issue=4 |pages=1241–9 |date=February 2004 |pmid=14977821 |doi= |url=}}</ref>
**Growth factor receptors without intrinsic [[tyrosine kinase]] activity:
***These depend upon [[intracellular]] [[kinases]] of the Src and [[Janus kinase]] ([[JAK]]) families. Examples include the [[JAK-STAT pathway]].<ref name="pmid11248555">{{cite journal |vauthors=Ihle JN |title=The Stat family in cytokine signaling |journal=Curr. Opin. Cell Biol. |volume=13 |issue=2 |pages=211–7 |date=April 2001 |pmid=11248555 |doi= |url=}}</ref>
 
===Pathophysiology of Acute Myeloid Leukemia===
*The malignant cell in acute myeloid leukemia is the [[myeloblast]]. However, in acute myeloid leukemia a single myeloblast accumulates genetic changes, which "freeze" the cell in its immature state and prevent [[cellular differentiation|differentiation]].<ref>Fialkow PJ: Clonal origin of human tumors. ''Biochim Biophys Acta'' 1976;458:283–321. PMID 1067873 </ref>  
*This type of mutation alone does not cause leukemia. However, when such a differentiation arrest is [[Knudson hypothesis|combined with other mutations]], which disrupt genes controlling [[cell growth|proliferation]], the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of acute myeloid leukemia.<ref>Fialkow PJ, Janssen JW, Bartram CR: Clonal remissions in acute nonlymphocytic leukemia: Evidence for a multistep pathogenesis of the malignancy. ''Blood'' 1991;77:1415–1517. PMID 2009365</ref>
*Much of the diversity and heterogeneity of acute myeloid leukemia stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway.<ref>Bonnet D, Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. ''Nat Med'' 1997;3:730–737. PMID 9212098</ref>
*Human acute myeloid leukemia is organized as a hierarchy, and the cancer stem cell hypothesis best models the pathophysiology of acute myeloid leukemia.
*Modern classification schemes for acute myeloid leukemia recognize that the characteristics and behavior of the leukemic cell (and the leukemia) may depend on the stage at which differentiation was halted.


* Much of the diversity and heterogeneity of acute myeloid leukemia stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway.<ref>Bonnet D, Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. ''Nat Med'' 1997;3:730–737. PMID 9212098</ref>  
===='''Role of Altered Signal Transduction and Autonomous Proliferation (Protein Tyrosine Kinase Activation)'''====
*Activation of [[tyrosine kinase]] receptors is followed by [[signal transduction]] via [[intracellular]] signal cascades leading to alteration of [[transcription]] within the [[cell nucleus]].<ref name="pmid11057895">{{cite journal |vauthors=Schlessinger J |title=Cell signaling by receptor tyrosine kinases |journal=Cell |volume=103 |issue=2 |pages=211–25 |date=October 2000 |pmid=11057895 |doi= |url=}}</ref>
*An important pathway that leads to cellular proliferation is the [[Ras (protein)|Ras-MAP Kinase pathway]], where [[Ras gene|Ras]] is activated by binding of [[guanosine triphosphate]] ([[Guanosine triphosphate|GTP]]). [[Ras]]-bound [[Guanosine|GTP]] in turn triggers a cascade of events that finally lead to activation of [[serine]]/[[threonine]] [[kinases]].
*Consequently, there is an activation of [[MAP kinases]], which [[phosphorylate]] important [[Transcriptional regulation|transcriptional]] regulators of [[cell cycle]].<ref name="pmid8316835">{{cite journal |vauthors=Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J |title=The function of GRB2 in linking the insulin receptor to Ras signaling pathways |journal=Science |volume=260 |issue=5116 |pages=1953–5 |date=June 1993 |pmid=8316835 |doi= |url=}}</ref><ref name="pmid8479541">{{cite journal |vauthors=Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J |title=Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling |journal=Nature |volume=363 |issue=6424 |pages=85–8 |date=May 1993 |pmid=8479541 |doi=10.1038/363085a0 |url=}}</ref><ref name="pmid1465135">{{cite journal |vauthors=Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T |title=Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases |journal=Nature |volume=360 |issue=6405 |pages=689–92 |date=December 1992 |pmid=1465135 |doi=10.1038/360689a0 |url=}}</ref><ref name="pmid8562934">{{cite journal |vauthors=Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P, Witte L, Borowitz MJ, Civin CI, Small D |title=Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias |journal=Blood |volume=87 |issue=3 |pages=1089–96 |date=February 1996 |pmid=8562934 |doi= |url=}}</ref>
* As a consequence of these, there is autonomous increased proliferation of cells.


* Modern classification schemes for acute myeloid leukemia recognize that the characteristics and behavior of the leukemic cell (and the leukemia) may depend on the stage at which differentiation was halted.
===='''Role of Altered Gene Expression and Differentiation Blockade'''====
*Altered [[gene expression]] leads to autonomous [[Cell proliferation|cellular proliferation]] with defects in regulatory pathways involved in [[Cell proliferation|cellular proliferation]].
*[[Chromosomal translocation|Chromosomal translocations]] and [[point mutations]] both play a pivotal role in generating a differentiation blockade on [[myeloid cells]].
*This results in a disruption in [[transcription factors]].
*[[Transcription factors]] affected by [[Chromosomal aberration|chromosomal rearrangement]] (translocations) include:
**Core binding factor complex [t(8;21), ETO-AML1 fusion]
**Core binding factor complex [inv(16), CBFβ-MYH11 fusion]
**Chromosome 3 translocation [t(3;21), RUNX1-EVI1 fusion]<ref name="pmid12773394">{{cite journal |vauthors=Follows GA, Tagoh H, Lefevre P, Hodge D, Morgan GJ, Bonifer C |title=Epigenetic consequences of AML1-ETO action at the human c-FMS locus |journal=EMBO J. |volume=22 |issue=11 |pages=2798–809 |date=June 2003 |pmid=12773394 |pmc=156747 |doi=10.1093/emboj/cdg250 |url=}}</ref><ref name="pmid12732181">{{cite journal |vauthors=Hiebert SW, Reed-Inderbitzin EF, Amann J, Irvin B, Durst K, Linggi B |title=The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14ARF tumor suppressor |journal=Blood Cells Mol. Dis. |volume=30 |issue=2 |pages=177–83 |date=2003 |pmid=12732181 |doi= |url=}}</ref><ref name="pmid11283671">{{cite journal |vauthors=Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG |title=AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia |journal=Nat. Med. |volume=7 |issue=4 |pages=444–51 |date=April 2001 |pmid=11283671 |doi=10.1038/86515 |url=}}</ref>
**Retinoic acid receptor (RAR) fusion [t(15;17), PML-RARα fusion]<ref name="pmid9486655">{{cite journal |vauthors=Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG |title=Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia |journal=Nature |volume=391 |issue=6669 |pages=815–8 |date=February 1998 |pmid=9486655 |doi=10.1038/35901 |url=}}</ref><ref name="pmid9462740">{{cite journal |vauthors=He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP |title=Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL |journal=Nat. Genet. |volume=18 |issue=2 |pages=126–35 |date=February 1998 |pmid=9462740 |doi=10.1038/ng0298-126 |url=}}</ref>
**MLL rearrangement [Activator protein of [[Hox gene]] promoters; Hox gene promoters in turn promote self-renewal of immature myeloid cells]<ref name="pmid12453418">{{cite journal |vauthors=Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL |title=MLL targets SET domain methyltransferase activity to Hox gene promoters |journal=Mol. Cell |volume=10 |issue=5 |pages=1107–17 |date=November 2002 |pmid=12453418 |doi= |url=}}</ref>
**Hox proteins<ref name="pmid9443054">{{cite journal |vauthors=Thorsteinsdottir U, Sauvageau G, Humphries RK |title=Hox homeobox genes as regulators of normal and leukemic hematopoiesis |journal=Hematol. Oncol. Clin. North Am. |volume=11 |issue=6 |pages=1221–37 |date=December 1997 |pmid=9443054 |doi= |url=}}</ref><ref name="pmid8563752">{{cite journal |vauthors=Nakamura T, Largaespada DA, Shaughnessy JD, Jenkins NA, Copeland NG |title=Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias |journal=Nat. Genet. |volume=12 |issue=2 |pages=149–53 |date=February 1996 |pmid=8563752 |doi=10.1038/ng0296-149 |url=}}</ref>
*Point mutations in myeloid transcription factors include:
**C/EBPα<ref name="pmid11283671">{{cite journal |vauthors=Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG |title=AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia |journal=Nat. Med. |volume=7 |issue=4 |pages=444–51 |date=April 2001 |pmid=11283671 |doi=10.1038/86515 |url=}}</ref><ref name="pmid14616999">{{cite journal |vauthors=Tiesmeier J, Czwalinna A, Müller-Tidow C, Krauter J, Serve H, Heil G, Ganser A, Verbeek W |title=Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia |journal=Br. J. Haematol. |volume=123 |issue=3 |pages=413–9 |date=November 2003 |pmid=14616999 |doi= |url=}}</ref>
**PU.1<ref name="pmid12130514">{{cite journal |vauthors=Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG |title=Heterozygous PU.1 mutations are associated with acute myeloid leukemia |journal=Blood |volume=100 |issue=3 |pages=998–1007 |date=August 2002 |pmid=12130514 |doi= |url=}}</ref>


=== Normal Hematopoeisis ===
===='''Evasion of Apoptosis (Protein Tyrosine Kinase Activation)'''====
* Hematopoeisis is tightly regulated under physiological conditions via a number of lineage-specific growth factor and lineage-specific growth signalling pathways.
*The increased expression of Bcl-2 pro-survival molecule plays a key role in evasion of programmed cell death in AML.<ref name="pmid8916965">{{cite journal |vauthors=Lisovsky M, Estrov Z, Zhang X, Consoli U, Sanchez-Williams G, Snell V, Munker R, Goodacre A, Savchenko V, Andreeff M |title=Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax |journal=Blood |volume=88 |issue=10 |pages=3987–97 |date=November 1996 |pmid=8916965 |doi= |url=}}</ref>
* The differentiation of myeloid stem cells into mature myelocytes is controlled by lineage-specific transcription factors that regulate the expression of lineage-specific genes.
*PI 3-kinase activates the AKT serine/threonine kinase, and this kinase in turn phosphorylates BAD and releases the BCL-2 anti-apoptotic molecule.<ref name="pmid14663477">{{cite journal |vauthors=Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C |title=PI3K/Akt and apoptosis: size matters |journal=Oncogene |volume=22 |issue=56 |pages=8983–98 |date=December 2003 |pmid=14663477 |doi=10.1038/sj.onc.1207115 |url=}}</ref><ref name="pmid10469654">{{cite journal |vauthors=Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T |title=STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells |journal=EMBO J. |volume=18 |issue=17 |pages=4754–65 |date=September 1999 |pmid=10469654 |pmc=1171548 |doi=10.1093/emboj/18.17.4754 |url=}}</ref>
* Normal hematopoeisis is dependent upon specific growth factor receptors. The two key growth factor receptors involved are as following:
*The RUNX1-MTG8 fusion protein of AML represses the expression of p14''ARF'' and promotes destabilization of [[p53]] (a tumor suppressor gene).<ref name="pmid9765203">{{cite journal |vauthors=Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW |title=Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling |journal=Genes Dev. |volume=12 |issue=19 |pages=3008–19 |date=October 1998 |pmid=9765203 |pmc=317198 |doi= |url=}}</ref><ref name="pmid9529248">{{cite journal |vauthors=Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA |title=The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53 |journal=Cell |volume=92 |issue=6 |pages=713–23 |date=March 1998 |pmid=9529248 |doi= |url=}}</ref><ref name="pmid9529249">{{cite journal |vauthors=Zhang Y, Xiong Y, Yarbrough WG |title=ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways |journal=Cell |volume=92 |issue=6 |pages=725–34 |date=March 1998 |pmid=9529249 |doi= |url=}}</ref>
** Growth factor receptors with intrinsic tyrosine kinase activity (expressed on CD34+ hematopoietic progenitor cells, examples include, receptors for the platelet-derived growth factors (PDGFs) PDGFR A and B, the receptor for M-CSF, Fms, and the receptors for KL (SCF) and FL, Kit and Flt3)<ref name="pmid14977821">{{cite journal |vauthors=Müller-Tidow C, Schwäble J, Steffen B, Tidow N, Brandt B, Becker K, Schulze-Bahr E, Halfter H, Vogt U, Metzger R, Schneider PM, Büchner T, Brandts C, Berdel WE, Serve H |title=High-throughput analysis of genome-wide receptor tyrosine kinase expression in human cancers identifies potential novel drug targets |journal=Clin. Cancer Res. |volume=10 |issue=4 |pages=1241–9 |date=February 2004 |pmid=14977821 |doi= |url=}}</ref>
===='''Self-Renewal'''====
** Growth factor receptors without intrinsic tyrosine kinase activity and depend upon intracellular kinases of the Src and JAK families (examples include, the JAK-STAT pathway)<ref name="pmid11248555">{{cite journal |vauthors=Ihle JN |title=The Stat family in cytokine signaling |journal=Curr. Opin. Cell Biol. |volume=13 |issue=2 |pages=211–7 |date=April 2001 |pmid=11248555 |doi= |url=}}</ref>
*The myeloid cells in acute myeolid leukemia have an ability to self-renew without being committed to a specific cell lineage.<ref name="pmid11265752">{{cite journal |vauthors=Buchholz F, Refaeli Y, Trumpp A, Bishop JM |title=Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse |journal=EMBO Rep. |volume=1 |issue=2 |pages=133–9 |date=August 2000 |pmid=11265752 |pmc=1084259 |doi=10.1038/sj.embor.embor610 |url=}}</ref>
'''Role Altered Signal Transduction and Autonomous Proliferaion (Protein Tyrosine Kinase Activation)'''
*The self-renewing capacity of myeloid cells in AMLs is thought to be mediated by the following:
* Activation of tyrosine kinase receptors is followed by signal transduction via intracellular signal cascades leading to alteration of transcription within the cell nucleus.<ref name="pmid11057895">{{cite journal |vauthors=Schlessinger J |title=Cell signaling by receptor tyrosine kinases |journal=Cell |volume=103 |issue=2 |pages=211–25 |date=October 2000 |pmid=11057895 |doi= |url=}}</ref>
**Fusion of ALK tyrosine kinase with nucleophosmin protein (NPM)<ref name="pmid8562957">{{cite journal |vauthors=Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ |title=The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion |journal=Blood |volume=87 |issue=3 |pages=882–6 |date=February 1996 |pmid=8562957 |doi= |url=}}</ref>
* An important pathway that leads to cellular proliferation is the Ras-MAP Kinase pathway, where Ras is activated by binding of GTP. Ras-bound GTP in turn triggers a cascade of events that finally lead to activation of serine/threonine kinases. Consequently, there is an activation of MAP kinases, which phosphorylate important transcriptional regulators of cell cycle.<ref name="pmid8316835">{{cite journal |vauthors=Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J |title=The function of GRB2 in linking the insulin receptor to Ras signaling pathways |journal=Science |volume=260 |issue=5116 |pages=1953–5 |date=June 1993 |pmid=8316835 |doi= |url=}}</ref><ref name="pmid8479541">{{cite journal |vauthors=Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J |title=Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling |journal=Nature |volume=363 |issue=6424 |pages=85–8 |date=May 1993 |pmid=8479541 |doi=10.1038/363085a0 |url=}}</ref><ref name="pmid1465135">{{cite journal |vauthors=Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T |title=Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases |journal=Nature |volume=360 |issue=6405 |pages=689–92 |date=December 1992 |pmid=1465135 |doi=10.1038/360689a0 |url=}}</ref><ref name="pmid8562934">{{cite journal |vauthors=Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P, Witte L, Borowitz MJ, Civin CI, Small D |title=Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias |journal=Blood |volume=87 |issue=3 |pages=1089–96 |date=February 1996 |pmid=8562934 |doi= |url=}}</ref>  
**Mutation of FLT3-ITD<ref name="pmid9737679">{{cite journal |vauthors=Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T |title=Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product |journal=Leukemia |volume=12 |issue=9 |pages=1333–7 |date=September 1998 |pmid=9737679 |doi= |url=}}</ref><ref name="pmid12060771">{{cite journal |vauthors=Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP, Ley TJ, Gilliland DG |title=PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=12 |pages=8283–8 |date=June 2002 |pmid=12060771 |pmc=123059 |doi=10.1073/pnas.122233699 |url=}}</ref>
* As a consequence of these, there is autonomous increased proliferation of cells.
**RUNX1-MTG8, PML-RARα, and PLZF-RARα fusions can all induce the expression of β-catenin and γ-catenin (plako-globin) proteins<ref name="Muller-TidowSteffen2004">{{cite journal|last1=Muller-Tidow|first1=C.|last2=Steffen|first2=B.|last3=Cauvet|first3=T.|last4=Tickenbrock|first4=L.|last5=Ji|first5=P.|last6=Diederichs|first6=S.|last7=Sargin|first7=B.|last8=Kohler|first8=G.|last9=Stelljes|first9=M.|last10=Puccetti|first10=E.|last11=Ruthardt|first11=M.|last12=deVos|first12=S.|last13=Hiebert|first13=S. W.|last14=Koeffler|first14=H. P.|last15=Berdel|first15=W. E.|last16=Serve|first16=H.|title=Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells|journal=Molecular and Cellular Biology|volume=24|issue=7|year=2004|pages=2890–2904|issn=0270-7306|doi=10.1128/MCB.24.7.2890-2904.2004}}</ref><ref>{{cite journal|doi=10.1101/gad.14.11.1319}}</ref>
'''Role of Altered Gene Expression and Differentiation Blockade'''
**The Wnt signalling pathway has also been shown to be involved in self-renewal of myeloid cells<ref name="pmid9160667">{{cite journal |vauthors=Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W |title=A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells |journal=Blood |volume=89 |issue=10 |pages=3624–35 |date=May 1997 |pmid=9160667 |doi= |url=}}</ref>
* Altered gene expression leads to autonomous cell proliferation with defect in regulatory pathways involved in cellular proliferation.
* Chromosomal translocations and point mutations. These processes play pivotal role in generating a differentiation blockade on myeloid cells.
* This results in a disruption in transcription factors..
* Transcription factors affected by chromosomal rearrangement (translocations) include:
** Core binding factor complex [t(8;21)-Runx1-MTG8 fusion; Inversion of chromosome 16-yielding the CBFβ-MYH11 fusion; t(3,21)-generating the RUNX1-EVI1 fusion]<ref name="pmid12773394">{{cite journal |vauthors=Follows GA, Tagoh H, Lefevre P, Hodge D, Morgan GJ, Bonifer C |title=Epigenetic consequences of AML1-ETO action at the human c-FMS locus |journal=EMBO J. |volume=22 |issue=11 |pages=2798–809 |date=June 2003 |pmid=12773394 |pmc=156747 |doi=10.1093/emboj/cdg250 |url=}}</ref><ref name="pmid12732181">{{cite journal |vauthors=Hiebert SW, Reed-Inderbitzin EF, Amann J, Irvin B, Durst K, Linggi B |title=The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14ARF tumor suppressor |journal=Blood Cells Mol. Dis. |volume=30 |issue=2 |pages=177–83 |date=2003 |pmid=12732181 |doi= |url=}}</ref><ref name="pmid11283671">{{cite journal |vauthors=Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG |title=AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia |journal=Nat. Med. |volume=7 |issue=4 |pages=444–51 |date=April 2001 |pmid=11283671 |doi=10.1038/86515 |url=}}</ref>
** Retinoic acid receptor (RAR) [t(15;17), which generates the PML-RARα fusion]<ref name="pmid9486655">{{cite journal |vauthors=Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG |title=Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia |journal=Nature |volume=391 |issue=6669 |pages=815–8 |date=February 1998 |pmid=9486655 |doi=10.1038/35901 |url=}}</ref><ref name="pmid9462740">{{cite journal |vauthors=He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP |title=Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL |journal=Nat. Genet. |volume=18 |issue=2 |pages=126–35 |date=February 1998 |pmid=9462740 |doi=10.1038/ng0298-126 |url=}}</ref>
** MLL protein [Activator protein of Hox gene promoters, Hox gene promoters in turn promote self-renewal of immature myeloid cells]<ref name="pmid12453418">{{cite journal |vauthors=Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL |title=MLL targets SET domain methyltransferase activity to Hox gene promoters |journal=Mol. Cell |volume=10 |issue=5 |pages=1107–17 |date=November 2002 |pmid=12453418 |doi= |url=}}</ref>
** Hox proteins<ref name="pmid9443054">{{cite journal |vauthors=Thorsteinsdottir U, Sauvageau G, Humphries RK |title=Hox homeobox genes as regulators of normal and leukemic hematopoiesis |journal=Hematol. Oncol. Clin. North Am. |volume=11 |issue=6 |pages=1221–37 |date=December 1997 |pmid=9443054 |doi= |url=}}</ref><ref name="pmid8563752">{{cite journal |vauthors=Nakamura T, Largaespada DA, Shaughnessy JD, Jenkins NA, Copeland NG |title=Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias |journal=Nat. Genet. |volume=12 |issue=2 |pages=149–53 |date=February 1996 |pmid=8563752 |doi=10.1038/ng0296-149 |url=}}</ref>
* Point mutations in myeloid transcription factors include:
** C/EBPα<ref name="pmid11283671">{{cite journal |vauthors=Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG |title=AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia |journal=Nat. Med. |volume=7 |issue=4 |pages=444–51 |date=April 2001 |pmid=11283671 |doi=10.1038/86515 |url=}}</ref><ref name="pmid14616999">{{cite journal |vauthors=Tiesmeier J, Czwalinna A, Müller-Tidow C, Krauter J, Serve H, Heil G, Ganser A, Verbeek W |title=Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia |journal=Br. J. Haematol. |volume=123 |issue=3 |pages=413–9 |date=November 2003 |pmid=14616999 |doi= |url=}}</ref>
** PU.1<ref name="pmid12130514">{{cite journal |vauthors=Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG |title=Heterozygous PU.1 mutations are associated with acute myeloid leukemia |journal=Blood |volume=100 |issue=3 |pages=998–1007 |date=August 2002 |pmid=12130514 |doi= |url=}}</ref>
'''Evasion of Apoptosis (Protein Tyrosine Kinase Activation)'''
* The increased expression of Bcl-2 pro-survival molecule plays a key role in evasion of programmed cell death in AML.<ref name="pmid8916965">{{cite journal |vauthors=Lisovsky M, Estrov Z, Zhang X, Consoli U, Sanchez-Williams G, Snell V, Munker R, Goodacre A, Savchenko V, Andreeff M |title=Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax |journal=Blood |volume=88 |issue=10 |pages=3987–97 |date=November 1996 |pmid=8916965 |doi= |url=}}</ref>
* PI 3-kinase activate the AKT serine/threonine kinase, and this kinase in turn phosphorylates BAD and releases the BCL-2 anti-apoptotic molecule<ref name="pmid14663477">{{cite journal |vauthors=Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C |title=PI3K/Akt and apoptosis: size matters |journal=Oncogene |volume=22 |issue=56 |pages=8983–98 |date=December 2003 |pmid=14663477 |doi=10.1038/sj.onc.1207115 |url=}}</ref><ref name="pmid10469654">{{cite journal |vauthors=Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T |title=STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells |journal=EMBO J. |volume=18 |issue=17 |pages=4754–65 |date=September 1999 |pmid=10469654 |pmc=1171548 |doi=10.1093/emboj/18.17.4754 |url=}}</ref>
* The RUNX1-MTG8 fusion protein of AML represses the expression of p14''ARF'' and promotes destabilization of p53 (a tumor supressor gene)<ref name="pmid9765203">{{cite journal |vauthors=Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW |title=Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling |journal=Genes Dev. |volume=12 |issue=19 |pages=3008–19 |date=October 1998 |pmid=9765203 |pmc=317198 |doi= |url=}}</ref><ref name="pmid9529248">{{cite journal |vauthors=Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA |title=The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53 |journal=Cell |volume=92 |issue=6 |pages=713–23 |date=March 1998 |pmid=9529248 |doi= |url=}}</ref><ref name="pmid9529249">{{cite journal |vauthors=Zhang Y, Xiong Y, Yarbrough WG |title=ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways |journal=Cell |volume=92 |issue=6 |pages=725–34 |date=March 1998 |pmid=9529249 |doi= |url=}}</ref>
'''Self-Renewal'''
* The myeloid cells in acute myeolid leukemia have an ability to self-renew without being committed to a specific cell lineage.<ref name="pmid11265752">{{cite journal |vauthors=Buchholz F, Refaeli Y, Trumpp A, Bishop JM |title=Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse |journal=EMBO Rep. |volume=1 |issue=2 |pages=133–9 |date=August 2000 |pmid=11265752 |pmc=1084259 |doi=10.1038/sj.embor.embor610 |url=}}</ref>
* The self-renewing capacity of myeloid cells in AMLs is thought to be mediated via the following:
** Fusion of ALK tyrosine kinase with nucleophosmin protein (NPM)<ref name="pmid8562957">{{cite journal |vauthors=Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ |title=The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion |journal=Blood |volume=87 |issue=3 |pages=882–6 |date=February 1996 |pmid=8562957 |doi= |url=}}</ref>
** Mutated FLT3-ITD<ref name="pmid9737679">{{cite journal |vauthors=Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T |title=Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product |journal=Leukemia |volume=12 |issue=9 |pages=1333–7 |date=September 1998 |pmid=9737679 |doi= |url=}}</ref><ref name="pmid12060771">{{cite journal |vauthors=Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP, Ley TJ, Gilliland DG |title=PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=12 |pages=8283–8 |date=June 2002 |pmid=12060771 |pmc=123059 |doi=10.1073/pnas.122233699 |url=}}</ref>
** RUNX1-MTG8, PML-RARα , and PLZF-RARα fusions can all induce the expression of β-catenin and γ-catenin (plako-globin) proteins<ref name="Muller-TidowSteffen2004">{{cite journal|last1=Muller-Tidow|first1=C.|last2=Steffen|first2=B.|last3=Cauvet|first3=T.|last4=Tickenbrock|first4=L.|last5=Ji|first5=P.|last6=Diederichs|first6=S.|last7=Sargin|first7=B.|last8=Kohler|first8=G.|last9=Stelljes|first9=M.|last10=Puccetti|first10=E.|last11=Ruthardt|first11=M.|last12=deVos|first12=S.|last13=Hiebert|first13=S. W.|last14=Koeffler|first14=H. P.|last15=Berdel|first15=W. E.|last16=Serve|first16=H.|title=Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells|journal=Molecular and Cellular Biology|volume=24|issue=7|year=2004|pages=2890–2904|issn=0270-7306|doi=10.1128/MCB.24.7.2890-2904.2004}}</ref><ref>{{cite journal|doi=10.1101/gad.14.11.1319}}</ref>
** The Wnt signalling pathway has also been shown to be involved in self-renewal of myeloid cells.<ref name="pmid9160667">{{cite journal |vauthors=Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W |title=A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells |journal=Blood |volume=89 |issue=10 |pages=3624–35 |date=May 1997 |pmid=9160667 |doi= |url=}}</ref>


==Genetics==
===Pathophysiology of Acute Promyelocytic Leukemia===
Specific [[cytogenetics|cytogenetic]] abnormalities can be found in many patients with acute myeloid leukemia; the types of chromosomal abnormalities often have [[prognosis|prognostic]] significance.<ref>Abeloff, Martin et al. (2004), pp. 2831&ndash;32.</ref>  The chromosomal [[translocations]] encode abnormal fusion [[proteins]], usually [[transcription factors]] whose altered properties may cause the "differentiation arrest."<ref>Greer, John P., et al. ''Wintrobe's Clinical Hematology'', 11th ed. Philadelphia: Lippincott, Williams, and Wilkins, 2004. p. 2045&ndash;2062</ref>  For example, in [[acute promyelocytic leukemia]], the t(15;17) translocation produces a PML-RARα [[fusion protein]] which binds to the [[retinoic acid]] receptor element in the promoters of several myeloid-specific genes and inhibits myeloid differentiation.<ref>Melnick A, Licht JD. Deconstructing a disease: RARα its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. ''Blood'' 1999;93:3167–3215. PMID 10233871</ref>. Acute myeloid leukemia M2 subtype is characterized by a [[translocation]] of a part of chromosome 8 to chromosome 21, written as t(8;21). On both sides of the chromosome, now containing pieces from two chromosomes, the DNA codes for different proteins. These two proteins are now being created as one single large protein, with a different effect in the body as the two proteins originally coded by the two different chromosomes. The two different proteins that are fused together are: [[RUNX1]] and ETO.


The clinical signs and symptoms of acute myeloid leukemia result from the fact that, as the leukemic clone of cells grows, it tends to displace or interfere with the development of normal blood cells in the bone marrow.<ref>Abeloff, Martin et al. (2004), p. 2828.</ref> This leads to [[neutropenia]], [[anemia]], and [[thrombocytopenia]].  The symptoms of acute myeloid leukemia are in turn often due to the low numbers of these normal blood elements.  In rare cases, patients can develop a ''[[chloroma]]'', or solid tumor of leukemic cells outside the bone marrow, which can cause various symptoms depending on its location.
* The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in [[hematopoietic stem cells]].
* The chromosomal translocation involves the juxtaposition of the retinoic acid receptor-alpha gene (''[[Retinoic acid receptor alpha|RARA]]'') on the long arm of chromosome 17 with another gene (most commonly the promyelocytic leukemia gene (''[[Promyelocyte|PML]]'') on the long arm of chromosome 15).<ref name="pmid28529810">{{cite journal| author=Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A| title=Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia. | journal=Case Rep Hematol | year= 2017 | volume= 2017 | issue=  | pages= 7657393 | pmid=28529810 | doi=10.1155/2017/7657393 | pmc=5424191 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28529810  }} </ref>
* The translocation is designated as t(15;17)(q22;q12). The ''PML-RARA'' fusion product is a transcriptional regulator and binds to [[retinoic acid]] response elements in the promoter regions of the genome. The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.<ref name="pmid26716387">{{cite journal| author=Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM| title=The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. | journal=Cancer | year= 2016 | volume= 122 | issue= 8 | pages= 1160-8 | pmid=26716387 | doi=10.1002/cncr.29852 | pmc=5042140 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26716387  }} </ref>
* This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells.
* The cells remain primitive and stem-like, which is the basis for the malignancy.
* The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.<ref name="pmid28529810">{{cite journal| author=Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A| title=Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia. | journal=Case Rep Hematol | year= 2017 | volume= 2017 | issue=  | pages= 7657393 | pmid=28529810 | doi=10.1155/2017/7657393 | pmc=5424191 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28529810  }} </ref>
* In 95% of cases of acute promyelocytic leukemia, the translocation involved ''PML'' and ''RARA''. However, it is important to note that ''RARA'' has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.
 
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center"
| valign="top" |
|+
! style="background: #4479BA; width: 200px;" |{{fontcolor|#FFF|Translocation Partner}}
! style="background: #4479BA; width: 400px;" |{{fontcolor|#FFF|Chromosomal Location}}
! style="background: #4479BA; width: 400px;" |{{fontcolor|#FFF|Function}}
! style="background: #4479BA; width: 400px;" |{{fontcolor|#FFF|Response to Therapy}}
! style="background: #4479BA; width: 400px;" |{{fontcolor|#FFF|Other Features}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
''PML''
| style="padding: 5px 5px; background: #F5F5F5;" |
15q24.1
| style="padding: 5px 5px; background: #F5F5F5;" |
*A member of the tripartite motif (TRIM) family
*Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor
*Regulate p53 response to oncogenic growth signals
*Influenced by the cell cycle
| style="padding: 5px 5px; background: #F5F5F5;" |
*Sensitive to all-''trans'' retinoic acid<ref name="pmid23556100">{{cite journal| author=Park J, Jurcic JG, Rosenblat T, Tallman MS| title=Emerging new approaches for the treatment of acute promyelocytic leukemia. | journal=Ther Adv Hematol | year= 2011 | volume= 2 | issue= 5 | pages= 335-52 | pmid=23556100 | doi=10.1177/2040620711410773 | pmc=3573416 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23556100  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
*Most common translocation
*Found in 70-90% of cases<ref name="pmid29541170">{{cite journal| author=Chen C, Huang X, Wang K, Chen K, Gao D, Qian S| title=Early mortality in acute promyelocytic leukemia: Potential predictors. | journal=Oncol Lett | year= 2018 | volume= 15 | issue= 4 | pages= 4061-4069 | pmid=29541170 | doi=10.3892/ol.2018.7854 | pmc=5835847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29541170  }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
''PLZF'' (''ZBTB16'')<ref name="pmid28529810">{{cite journal| author=Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A| title=Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia. | journal=Case Rep Hematol | year= 2017 | volume= 2017 | issue=  | pages= 7657393 | pmid=28529810 | doi=10.1155/2017/7657393 | pmc=5424191 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28529810  }} </ref><ref name="pmid29541170">{{cite journal| author=Chen C, Huang X, Wang K, Chen K, Gao D, Qian S| title=Early mortality in acute promyelocytic leukemia: Potential predictors. | journal=Oncol Lett | year= 2018 | volume= 15 | issue= 4 | pages= 4061-4069 | pmid=29541170 | doi=10.3892/ol.2018.7854 | pmc=5835847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29541170  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
11q23.2
| style="padding: 5px 5px; background: #F5F5F5;" |
*Encodes a zinc finger transcription factor
*Involved in cell cycle regulation
*Interacts with histone deacetylases
| style="padding: 5px 5px; background: #F5F5F5;" |
*Resistant to all-''trans'' retinoic acid<ref name="pmid23556100">{{cite journal| author=Park J, Jurcic JG, Rosenblat T, Tallman MS| title=Emerging new approaches for the treatment of acute promyelocytic leukemia. | journal=Ther Adv Hematol | year= 2011 | volume= 2 | issue= 5 | pages= 335-52 | pmid=23556100 | doi=10.1177/2040620711410773 | pmc=3573416 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23556100  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
*Second most common translocation (after ''PML-RARA'')
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
''NPM1''
| style="padding: 5px 5px; background: #F5F5F5;" |
5q35.1
| style="padding: 5px 5px; background: #F5F5F5;" |
*Encodes nucleophosmin 1 (a nucleolar shuttle protein)
*Involved in centromere duplication
*Serves a protein chaperone
*Regulates the cell cycle
*Sequesters the tumor suppressor ''ARF'' in the nucleus and protects ''ARF'' from degradation
| style="padding: 5px 5px; background: #F5F5F5;" |
*Sensitive to all-''trans'' retinoic acid<ref name="pmid23556100">{{cite journal| author=Park J, Jurcic JG, Rosenblat T, Tallman MS| title=Emerging new approaches for the treatment of acute promyelocytic leukemia. | journal=Ther Adv Hematol | year= 2011 | volume= 2 | issue= 5 | pages= 335-52 | pmid=23556100 | doi=10.1177/2040620711410773 | pmc=3573416 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23556100  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
*''NPM1'' mutation carries a favorable prognosis in [[acute myeloid leukemia]]
*Rare translocation
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
''NUMA''<ref name="pmid23556100">{{cite journal| author=Park J, Jurcic JG, Rosenblat T, Tallman MS| title=Emerging new approaches for the treatment of acute promyelocytic leukemia. | journal=Ther Adv Hematol | year= 2011 | volume= 2 | issue= 5 | pages= 335-52 | pmid=23556100 | doi=10.1177/2040620711410773 | pmc=3573416 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23556100 }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
11q13.4
| style="padding: 5px 5px; background: #F5F5F5;" |
*Contributes to a structural component of the nuclear matrix
*Interacts with microtubules
*Contributes to mitotic spindle formation during cell division
| style="padding: 5px 5px; background: #F5F5F5;" |
*Sensitive to all-''trans'' retinoic acid<ref name="pmid23556100">{{cite journal| author=Park J, Jurcic JG, Rosenblat T, Tallman MS| title=Emerging new approaches for the treatment of acute promyelocytic leukemia. | journal=Ther Adv Hematol | year= 2011 | volume= 2 | issue= 5 | pages= 335-52 | pmid=23556100 | doi=10.1177/2040620711410773 | pmc=3573416 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23556100 }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
*Rare translocation
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
''STAT5B''<ref name="pmid29541170">{{cite journal| author=Chen C, Huang X, Wang K, Chen K, Gao D, Qian S| title=Early mortality in acute promyelocytic leukemia: Potential predictors. | journal=Oncol Lett | year= 2018 | volume= 15 | issue= 4 | pages= 4061-4069 | pmid=29541170 | doi=10.3892/ol.2018.7854 | pmc=5835847 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29541170  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
17q21.2
| style="padding: 5px 5px; background: #F5F5F5;" |
*Encodes a signal transducer and activator of transcription (STAT)
*Serves an intracellular transduction molecule for cytokine signaling
*Translocates to the nucleus and functions as a transcription factor
*Involved in T cell receptor signaling
*Involved in [[apoptosis]]
*Sequesters the tumor suppressor ''ARF'' in the nucleus and protects ''ARF'' from degradation
| style="padding: 5px 5px; background: #F5F5F5;" |
*Resistant to all-''trans'' retinoic acid<ref name="pmid23556100">{{cite journal| author=Park J, Jurcic JG, Rosenblat T, Tallman MS| title=Emerging new approaches for the treatment of acute promyelocytic leukemia. | journal=Ther Adv Hematol | year= 2011 | volume= 2 | issue= 5 | pages= 335-52 | pmid=23556100 | doi=10.1177/2040620711410773 | pmc=3573416 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23556100  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
*Rare translocation
|-
|}


==Microscopic Pathology==
==Microscopic Pathology==


Description of pictures according the classification of Acute myeloid leukemia system.
Description of pictures (shown below) according the classification of Acute myeloid leukemia system.
====Acute myeloid leukemia M0 classification====
====Acute myeloid leukemia- M0 classification====
* Acute myeloid leukemia M0 with lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts. Morphologically, blasts are small to large with no granules or Auer rods.
* Acute myeloid leukemia M0 with lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts
* Acute myeloid leukemia-M1 with presence of more than 90% myeloblasts in blood.
* Morphologically, blasts are small to large with no granules or Auer rods
* Acute myeloid leukemia-M1 peroxidase.


====Acute myeloid leukemia M2 classification====
[[File:AML 0.png|center|thumb|Acute myeloid leukemia-M0 - lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts. Morphologically, blasts are small to large with no granules or Auer rods. I'''mages shown  are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Ja'''pan]]
* Acute myeloid leukemia-M2: Presence of granules can be noted.
<br />
* Acute myeloid leukemia-M2: Large myeloblasts with prominent nucleoli.
====Acute myeloid leukemia- M1 classification====
* Presence of more than 90% myeloblasts in blood
* Peroxidase


====Acute myeloid leukemia M3 classification====
[[File:AML-M1 0001.jpg|center|thumb|'''Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan''']]
* Acute myeloid leukemia-M3: Also called promyelocytic leukemia. Hypergranular morphology with most cells containing abundant large granules.
<br />
* Acute myeloid leukemia-M3: Ruptured cells are releasing their granules free onto the slide. Presence of Auer rods can be noticed.
====Acute myeloid leukemia- M2 classification====
* Presence of granules can be noted
* Large myeloblasts with prominent nucleoli


====Acute myeloid leukemia M5a and M5b classification====
[[File:AML-M2 0001.jpg|center|thumb|'''Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan'''
* Acute myeloid leukemia-M5a: >80% monoblasts in the marrow.
* Acute myeloid leukemia-M5a: large monoblasts with fine nuclear chromatin and prominent nucleoli. Note the absence of Auer rods.
* Acute myeloid leukemia-M5b: <80% monoblasts in the marrow.


====Acute myeloid leukemia M7 classification====
AML-M2 -  large myeloblasts with prominent nucleoli.]]
* Acute myeloid leukemia-M7: Irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present.
<br />
====Acute myeloid leukemia- M3 classification====
* Also known as promyelocytic leukemia
* Hypergranular morphology with most cells containing abundant large granules
* Ruptured cells are releasing their granules free onto the slide
* Presence of Auer rods can be noticed
 
[[File:AML-M3 0001.jpg|center|thumb|'''Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan'''.
 
AML-M3 - polarity of cytoplasmic granulation. In many cells the granules tend to polarize toward one portion of the cytoplasm and the nucleus on the opposite side.]]
<br />
====Acute myeloid leukemia- M5a and M5b classification====
* M5a: >80% monoblasts in the marrow
* M5a: large monoblasts with fine nuclear chromatin and prominent nucleoli (note the absence of Auer rods)
* M5b: <80% monoblasts in the marrow
 
[[File:AML-M5a 0001.jpg|center|thumb|'''Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan'''.
 
M5b: <80% monoblasts in the marrow]]
[[File:AML-M5a 0001.jpg|center|thumb|'''Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan'''.
 
M5a: >80% monoblasts in the marrow]]
<br />
====Acute myeloid leukemia- M7 classification====
* Irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present
**Megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio
**Megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio
**Nuclear chromatin is dense and homogeneous
**Nuclear chromatin is dense and homogeneous
Line 92: Line 215:
**Immunophenotyping using MoAb to megakaryocytic restricted antigen (CD41 and CD61) may be diagnostic
**Immunophenotyping using MoAb to megakaryocytic restricted antigen (CD41 and CD61) may be diagnostic


(Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan)
[[File:AML-M7 0001.jpg|center|thumb|'''Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan'''AML-M7 - irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present.]]
<gallery widths="200px">
<br />
Image:AML 0.png|Acute myeloid leukemia-M0 - lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts. Morphologically, blasts are small to large with no granules or Auer rods.
Image:Acute myeloid leukemia-M1 0002.jpg|Acute myeloid leukemia-M1 - presence of more than 90% myeloblasts in blood.
Image:Acute myeloid leukemia-M1 peroxidase 0001.jpg|Acute myeloid leukemia-M1 peroxidase.
Image:Acute myeloid leukemia-M1 0005.jpg|Acute myeloid leukemia-M1 - more cytoplasm than M0, but still no granules.
Image:Acute myeloid leukemia-M1 0004.jpg|Acute myeloid leukemia-M1.
Image:Acute myeloid leukemia-M1 0003.jpg|Acute myeloid leukemia-M1.
Image:AML-M2 0002.jpg|AML-M2 - presence of granules can be noted.
Image:AML-M2 0001.jpg|AML-M2 -  large myeloblasts with prominent nucleoli.
Image:AML-M2 0004.jpg|AML-M2 - maturing myeloid elements including band and segmented neutrophils in the background.
Image:AML-M2 0003.jpg|AML-M2 - presence of a few maturing myeloid elements.
Image:AML-M3 0006.jpg|AML-M3 - also called promyelocytic leukemia. Hypergranular morphology with most cells containing abundant large granules.
Image:AML-M3 0004.jpg|AML-M3 - ruptured cells are releasing their granules free onto the slide. Presence of Auer rods can be noticed.
Image:AML-M3 0002.jpg|AML-M3 - presence of abundant fine granules.
Image:AML-M3 0001.jpg|AML-M3 - polarity of cytoplasmic granulation. In many cells the granules tend to polarize toward one portion of the cytoplasm and the nucleus on the opposite side.
Image:AML-M3 Auer bodies 0005.jpg|AML-M3 Auer bodies.
Image:AML-M3 Auer bodies 0003.jpg|AML-M3 Auer bodies.
Image:AML-M3 variation 0007.jpg|AML-M3 variation.
Image:AML-M4 0001.jpg|AML-M4 - large monoblasts with abundant cytoplasm and moderately to intensely basophilic. The monoblasts will have lacy nuclear chromatin and one or more predominant nucleoli.
Image:AML-M5a 0003.jpg|AML-M5a - >80% monoblasts in the marrow.
Image:AML-M5a 0001.jpg|AML-M5a -  large monoblasts with fine nuclear chromatin and prominent nucleoli. Note the absence of Auer rods.
Image:AML-M5a alpha naphtyle acetat 0002.jpg|AML-M5a (alpha naphtyle acetat).
Image:AML-M5b 0001.jpg|AML-M5b - <80% monoblasts in the marrow.
Image:AML-M5b 0002.jpg|AML-M5b - moderate amounts of cytoplasm and large nuclei with fine chromatin but without prominent nucleoli. Note presence of nuclear folds and creases, which are a characteristic feature of promonocytes.
Image:AML-M7 0001.jpg|AML-M7 - irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present.
Image:AML-M7 CD41 0001.jpg|AML-M7 - megakaryoblasts are usually medium sized to large cells with a high nuclear-cytoplasmic ratio. Nuclear chromatin is dense and homogeneous.
</gallery>
 
==References==
==References==
{{reflist|2}}
{{reflist|2}}

Latest revision as of 17:32, 29 October 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2], Raviteja Guddeti, M.B.B.S. [3], Carlos A Lopez, M.D. [4], Shyam Patel [5]; Grammar Reviewer: Natalie Harpenau, B.S.[6]

Overview

Normal hematopoiesis involves the production of blood cells, and this normal physiologic process is dysregulated in acute myeloid leukemia. The pathophysiology of acute myeloid leukemia involves multiple mechanisms, including altered signal transduction and autonomous proliferation, differentiation blockade, evasion of apoptosis, and self-renewal. The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene production causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.

Pathophysiology

In order to understand the pathophysiology of acute myeloid leukemia, it is important to understand normal physiology of hematopoiesis or blood cell production.

Normal Hematopoiesis

Pathophysiology of Acute Myeloid Leukemia

  • The malignant cell in acute myeloid leukemia is the myeloblast. However, in acute myeloid leukemia a single myeloblast accumulates genetic changes, which "freeze" the cell in its immature state and prevent differentiation.[3]
  • This type of mutation alone does not cause leukemia. However, when such a differentiation arrest is combined with other mutations, which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of acute myeloid leukemia.[4]
  • Much of the diversity and heterogeneity of acute myeloid leukemia stems from the fact that leukemic transformation can occur at a number of different steps along the differentiation pathway.[5]
  • Human acute myeloid leukemia is organized as a hierarchy, and the cancer stem cell hypothesis best models the pathophysiology of acute myeloid leukemia.
  • Modern classification schemes for acute myeloid leukemia recognize that the characteristics and behavior of the leukemic cell (and the leukemia) may depend on the stage at which differentiation was halted.

Role of Altered Signal Transduction and Autonomous Proliferation (Protein Tyrosine Kinase Activation)

Role of Altered Gene Expression and Differentiation Blockade

Evasion of Apoptosis (Protein Tyrosine Kinase Activation)

  • The increased expression of Bcl-2 pro-survival molecule plays a key role in evasion of programmed cell death in AML.[21]
  • PI 3-kinase activates the AKT serine/threonine kinase, and this kinase in turn phosphorylates BAD and releases the BCL-2 anti-apoptotic molecule.[22][23]
  • The RUNX1-MTG8 fusion protein of AML represses the expression of p14ARF and promotes destabilization of p53 (a tumor suppressor gene).[24][25][26]

Self-Renewal

  • The myeloid cells in acute myeolid leukemia have an ability to self-renew without being committed to a specific cell lineage.[27]
  • The self-renewing capacity of myeloid cells in AMLs is thought to be mediated by the following:
    • Fusion of ALK tyrosine kinase with nucleophosmin protein (NPM)[28]
    • Mutation of FLT3-ITD[29][30]
    • RUNX1-MTG8, PML-RARα, and PLZF-RARα fusions can all induce the expression of β-catenin and γ-catenin (plako-globin) proteins[31][32]
    • The Wnt signalling pathway has also been shown to be involved in self-renewal of myeloid cells[33]

Pathophysiology of Acute Promyelocytic Leukemia

  • The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.
  • The chromosomal translocation involves the juxtaposition of the retinoic acid receptor-alpha gene (RARA) on the long arm of chromosome 17 with another gene (most commonly the promyelocytic leukemia gene (PML) on the long arm of chromosome 15).[34]
  • The translocation is designated as t(15;17)(q22;q12). The PML-RARA fusion product is a transcriptional regulator and binds to retinoic acid response elements in the promoter regions of the genome. The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.[35]
  • This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells.
  • The cells remain primitive and stem-like, which is the basis for the malignancy.
  • The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.[34]
  • In 95% of cases of acute promyelocytic leukemia, the translocation involved PML and RARA. However, it is important to note that RARA has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.
Translocation Partner Chromosomal Location Function Response to Therapy Other Features

PML

15q24.1

  • A member of the tripartite motif (TRIM) family
  • Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor
  • Regulate p53 response to oncogenic growth signals
  • Influenced by the cell cycle
  • Sensitive to all-trans retinoic acid[36]
  • Most common translocation
  • Found in 70-90% of cases[37]

PLZF (ZBTB16)[34][37]

11q23.2

  • Encodes a zinc finger transcription factor
  • Involved in cell cycle regulation
  • Interacts with histone deacetylases
  • Resistant to all-trans retinoic acid[36]
  • Second most common translocation (after PML-RARA)

NPM1

5q35.1

  • Encodes nucleophosmin 1 (a nucleolar shuttle protein)
  • Involved in centromere duplication
  • Serves a protein chaperone
  • Regulates the cell cycle
  • Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation
  • Sensitive to all-trans retinoic acid[36]

NUMA[36]

11q13.4

  • Contributes to a structural component of the nuclear matrix
  • Interacts with microtubules
  • Contributes to mitotic spindle formation during cell division
  • Sensitive to all-trans retinoic acid[36]
  • Rare translocation

STAT5B[37]

17q21.2

  • Encodes a signal transducer and activator of transcription (STAT)
  • Serves an intracellular transduction molecule for cytokine signaling
  • Translocates to the nucleus and functions as a transcription factor
  • Involved in T cell receptor signaling
  • Involved in apoptosis
  • Sequesters the tumor suppressor ARF in the nucleus and protects ARF from degradation
  • Resistant to all-trans retinoic acid[36]
  • Rare translocation

Microscopic Pathology

Description of pictures (shown below) according the classification of Acute myeloid leukemia system.

Acute myeloid leukemia- M0 classification

  • Acute myeloid leukemia M0 with lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts
  • Morphologically, blasts are small to large with no granules or Auer rods
Acute myeloid leukemia-M0 - lack of obvious myeloid differentiation by routine histologic examination and presence of myeloperoxidase in <3% of blasts. Morphologically, blasts are small to large with no granules or Auer rods. Images shown are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan


Acute myeloid leukemia- M1 classification

  • Presence of more than 90% myeloblasts in blood
  • Peroxidase
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan


Acute myeloid leukemia- M2 classification

  • Presence of granules can be noted
  • Large myeloblasts with prominent nucleoli
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan AML-M2 - large myeloblasts with prominent nucleoli.


Acute myeloid leukemia- M3 classification

  • Also known as promyelocytic leukemia
  • Hypergranular morphology with most cells containing abundant large granules
  • Ruptured cells are releasing their granules free onto the slide
  • Presence of Auer rods can be noticed
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan. AML-M3 - polarity of cytoplasmic granulation. In many cells the granules tend to polarize toward one portion of the cytoplasm and the nucleus on the opposite side.


Acute myeloid leukemia- M5a and M5b classification

  • M5a: >80% monoblasts in the marrow
  • M5a: large monoblasts with fine nuclear chromatin and prominent nucleoli (note the absence of Auer rods)
  • M5b: <80% monoblasts in the marrow
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan. M5b: <80% monoblasts in the marrow
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - Japan. M5a: >80% monoblasts in the marrow


Acute myeloid leukemia- M7 classification

  • Irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present
    • Megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio
    • Nuclear chromatin is dense and homogeneous
    • Variable basophilic cytoplasm which may be vacuolated
    • An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present
    • Megakaryoblasts lack myeloperoxidase (MPO) activity and stain negatively with Sudan black B
    • Clumps or granules in the cytoplasm
    • PAS staining varies from negative to focal or granular positivity, to strongly positive staining
    • More precise identification is by immunophenotyping or with electron microscopy (EM)
    • Immunophenotyping using MoAb to megakaryocytic restricted antigen (CD41 and CD61) may be diagnostic
Images shown below are courtesy of Melih Aktan MD., Istanbul Medical Faculty - Turkey, and Kyoto University - JapanAML-M7 - irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present.


References

  1. ↑ Müller-Tidow C, Schwäble J, Steffen B, Tidow N, Brandt B, Becker K, Schulze-Bahr E, Halfter H, Vogt U, Metzger R, Schneider PM, Büchner T, Brandts C, Berdel WE, Serve H (February 2004). "High-throughput analysis of genome-wide receptor tyrosine kinase expression in human cancers identifies potential novel drug targets". Clin. Cancer Res. 10 (4): 1241–9. PMID 14977821.
  2. ↑ Ihle JN (April 2001). "The Stat family in cytokine signaling". Curr. Opin. Cell Biol. 13 (2): 211–7. PMID 11248555.
  3. ↑ Fialkow PJ: Clonal origin of human tumors. Biochim Biophys Acta 1976;458:283–321. PMID 1067873
  4. ↑ Fialkow PJ, Janssen JW, Bartram CR: Clonal remissions in acute nonlymphocytic leukemia: Evidence for a multistep pathogenesis of the malignancy. Blood 1991;77:1415–1517. PMID 2009365
  5. ↑ Bonnet D, Dick JE: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730–737. PMID 9212098
  6. ↑ Schlessinger J (October 2000). "Cell signaling by receptor tyrosine kinases". Cell. 103 (2): 211–25. PMID 11057895.
  7. ↑ Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J (June 1993). "The function of GRB2 in linking the insulin receptor to Ras signaling pathways". Science. 260 (5116): 1953–5. PMID 8316835.
  8. ↑ Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J (May 1993). "Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling". Nature. 363 (6424): 85–8. doi:10.1038/363085a0. PMID 8479541.
  9. ↑ Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T (December 1992). "Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases". Nature. 360 (6405): 689–92. doi:10.1038/360689a0. PMID 1465135.
  10. ↑ Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P, Witte L, Borowitz MJ, Civin CI, Small D (February 1996). "Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias". Blood. 87 (3): 1089–96. PMID 8562934.
  11. ↑ Follows GA, Tagoh H, Lefevre P, Hodge D, Morgan GJ, Bonifer C (June 2003). "Epigenetic consequences of AML1-ETO action at the human c-FMS locus". EMBO J. 22 (11): 2798–809. doi:10.1093/emboj/cdg250. PMC 156747. PMID 12773394.
  12. ↑ Hiebert SW, Reed-Inderbitzin EF, Amann J, Irvin B, Durst K, Linggi B (2003). "The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14ARF tumor suppressor". Blood Cells Mol. Dis. 30 (2): 177–83. PMID 12732181.
  13. ↑ 13.0 13.1 Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG (April 2001). "AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia". Nat. Med. 7 (4): 444–51. doi:10.1038/86515. PMID 11283671.
  14. ↑ Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG (February 1998). "Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia". Nature. 391 (6669): 815–8. doi:10.1038/35901. PMID 9486655.
  15. ↑ He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP (February 1998). "Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL". Nat. Genet. 18 (2): 126–35. doi:10.1038/ng0298-126. PMID 9462740.
  16. ↑ Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL (November 2002). "MLL targets SET domain methyltransferase activity to Hox gene promoters". Mol. Cell. 10 (5): 1107–17. PMID 12453418.
  17. ↑ Thorsteinsdottir U, Sauvageau G, Humphries RK (December 1997). "Hox homeobox genes as regulators of normal and leukemic hematopoiesis". Hematol. Oncol. Clin. North Am. 11 (6): 1221–37. PMID 9443054.
  18. ↑ Nakamura T, Largaespada DA, Shaughnessy JD, Jenkins NA, Copeland NG (February 1996). "Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias". Nat. Genet. 12 (2): 149–53. doi:10.1038/ng0296-149. PMID 8563752.
  19. ↑ Tiesmeier J, Czwalinna A, Müller-Tidow C, Krauter J, Serve H, Heil G, Ganser A, Verbeek W (November 2003). "Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia". Br. J. Haematol. 123 (3): 413–9. PMID 14616999.
  20. ↑ Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG (August 2002). "Heterozygous PU.1 mutations are associated with acute myeloid leukemia". Blood. 100 (3): 998–1007. PMID 12130514.
  21. ↑ Lisovsky M, Estrov Z, Zhang X, Consoli U, Sanchez-Williams G, Snell V, Munker R, Goodacre A, Savchenko V, Andreeff M (November 1996). "Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax". Blood. 88 (10): 3987–97. PMID 8916965.
  22. ↑ Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C (December 2003). "PI3K/Akt and apoptosis: size matters". Oncogene. 22 (56): 8983–98. doi:10.1038/sj.onc.1207115. PMID 14663477.
  23. ↑ Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T (September 1999). "STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells". EMBO J. 18 (17): 4754–65. doi:10.1093/emboj/18.17.4754. PMC 1171548. PMID 10469654.
  24. ↑ Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW (October 1998). "Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling". Genes Dev. 12 (19): 3008–19. PMC 317198. PMID 9765203.
  25. ↑ Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA (March 1998). "The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53". Cell. 92 (6): 713–23. PMID 9529248.
  26. ↑ Zhang Y, Xiong Y, Yarbrough WG (March 1998). "ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways". Cell. 92 (6): 725–34. PMID 9529249.
  27. ↑ Buchholz F, Refaeli Y, Trumpp A, Bishop JM (August 2000). "Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse". EMBO Rep. 1 (2): 133–9. doi:10.1038/sj.embor.embor610. PMC 1084259. PMID 11265752.
  28. ↑ Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ (February 1996). "The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion". Blood. 87 (3): 882–6. PMID 8562957.
  29. ↑ Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T (September 1998). "Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product". Leukemia. 12 (9): 1333–7. PMID 9737679.
  30. ↑ Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP, Ley TJ, Gilliland DG (June 2002). "PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model". Proc. Natl. Acad. Sci. U.S.A. 99 (12): 8283–8. doi:10.1073/pnas.122233699. PMC 123059. PMID 12060771.
  31. ↑ Muller-Tidow, C.; Steffen, B.; Cauvet, T.; Tickenbrock, L.; Ji, P.; Diederichs, S.; Sargin, B.; Kohler, G.; Stelljes, M.; Puccetti, E.; Ruthardt, M.; deVos, S.; Hiebert, S. W.; Koeffler, H. P.; Berdel, W. E.; Serve, H. (2004). "Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells". Molecular and Cellular Biology. 24 (7): 2890–2904. doi:10.1128/MCB.24.7.2890-2904.2004. ISSN 0270-7306.
  32. ↑ . doi:10.1101/gad.14.11.1319. Missing or empty |title= (help)
  33. ↑ Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W (May 1997). "A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells". Blood. 89 (10): 3624–35. PMID 9160667.
  34. ↑ 34.0 34.1 34.2 Langabeer SE, Preston L, Kelly J, Goodyer M, Elhassadi E, Hayat A (2017). "Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia". Case Rep Hematol. 2017: 7657393. doi:10.1155/2017/7657393. PMC 5424191. PMID 28529810.
  35. ↑ Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM (2016). "The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy". Cancer. 122 (8): 1160–8. doi:10.1002/cncr.29852. PMC 5042140. PMID 26716387.
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 Park J, Jurcic JG, Rosenblat T, Tallman MS (2011). "Emerging new approaches for the treatment of acute promyelocytic leukemia". Ther Adv Hematol. 2 (5): 335–52. doi:10.1177/2040620711410773. PMC 3573416. PMID 23556100.
  37. ↑ 37.0 37.1 37.2 Chen C, Huang X, Wang K, Chen K, Gao D, Qian S (2018). "Early mortality in acute promyelocytic leukemia: Potential predictors". Oncol Lett. 15 (4): 4061–4069. doi:10.3892/ol.2018.7854. PMC 5835847. PMID 29541170.

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