Acute promyelocytic leukemia pathophysiology: Difference between revisions
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{{Acute promyelocytic leukemia}} | {{Acute promyelocytic leukemia}} | ||
{{CMG}} {{shyam}} {{AE}} {{S.G.}} | {{CMG}} {{shyam}} {{AE}} {{S.G.}}; {{GRR}} {{Nat}} | ||
==Overview== | ==Overview== | ||
The [[pathophysiology]] of acute promyelocytic leukemia is most commonly due to a reciprocal [[Chromosomal translocation|translocation]] between [[chromosomes]] 15 and 17. The novel | The [[pathophysiology]] of acute promyelocytic leukemia is most commonly due to a reciprocal [[Chromosomal translocation|translocation]] between [[chromosomes]] 15 and 17. The novel gene product causes a [[differentiation]] block in [[myeloid]] [[Cell (biology)|cells]]. There are multiple different binding partners for the [[RARA gene|''RARA'' gene]], so multiple translocations can contribute to the pathogenesis of acute [[Promyelocytic leukemia protein|promyelocytic leukemia]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
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.<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 [[pathophysiology]] of acute promyelocytic leukemia begins with a balanced [[Reciprocal translocation|reciprocal]] [[chromosomal translocation]] in [[hematopoietic stem cells]].<ref name="ZelentGuidez2001">{{cite journal|last1=Zelent|first1=Arthur|last2=Guidez|first2=Fabien|last3=Melnick|first3=Ari|last4=Waxman|first4=Samuel|last5=Licht|first5=Jonathan D|title=Translocations of the RARα gene in acute promyelocytic leukemia|journal=Oncogene|volume=20|issue=49|year=2001|pages=7186–7203|issn=0950-9232|doi=10.1038/sj.onc.1204766}}</ref> | ||
* The [[chromosomal translocation]] involves the juxtaposition of the [[retinoic acid]] [[receptor]]- alpha gene (''[[RARA gene|RARA]]'') on the long arm of chromosome 17 with another gene, most commonly the promyelocytic leukemia gene (''[[Progressive multifocal leukoencephalopathy|PML]]'') on the long arm of chromosome 15. The translocation is designated as t(15;17)(q22;q12).<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>{{Cite journal | |||
| author = [[L. R. Hiorns]], [[T. Min]], [[G. J. Swansbury]], [[A. Zelent]], [[M. J. Dyer]] & [[D. Catovsky]] | |||
| title = Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17 | |||
| journal = [[Blood]] | |||
| volume = 83 | |||
| issue = 10 | |||
| pages = 2946–2951 | |||
| year = 1994 | |||
| month = May | |||
| pmid = 8180390 | |||
}}</ref> | |||
* | |||
* The ''PML-[[RARA gene|RARA]]'' [[Fusion gene|fusion]] product is a [[Transcriptional regulation|transcriptional]] [[Regulator gene|regulator]] and [[Binding (molecular)|binds]] to [[retinoic acid]] response elements in the [[Promoter region|promoter regions]] of the [[genome]]. | |||
* The PML-RARA fusion product serves to recruit co-repressors of [[gene]] [[Transcription (genetics)|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><ref name="urlRARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/gene/5914 |title=RARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI |format= |work= |accessdate=}}</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 (biology)|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 gene|RARA]]''. However, it is important to note that ''[[RARA gene|RARA]]'' has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.<ref name="SaeedLogie2011">{{cite journal|last1=Saeed|first1=S|last2=Logie|first2=C|last3=Stunnenberg|first3=H G|last4=Martens|first4=J H A|title=Genome-wide functions of PML–RARα in acute promyelocytic leukaemia|journal=British Journal of Cancer|volume=104|issue=4|year=2011|pages=554–558|issn=0007-0920|doi=10.1038/sj.bjc.6606095}}</ref> | |||
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center" | {| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center" | ||
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*A member of the tripartite motif (TRIM) family | *A member of the tripartite motif (TRIM) family | ||
*Localizes to nucleolar bodies and functions as a transcription factor and tumor suppressor | *Localizes to nucleolar bodies and functions as a [[transcription factor]] and [[tumor]] suppressor | ||
*Regulate p53 response to oncogenic growth signals | *Regulate p53 response to oncogenic growth signals | ||
*Influenced by the cell cycle | *Influenced by the [[Cell (biology)|cell]] cycle | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | 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> | *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;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Most common translocation | *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> | *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> | ||
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11q23.2 | 11q23.2 | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Encodes a zinc finger transcription factor | *Encodes a [[Zinc (element)|zinc]] finger [[Transcription (genetics)|transcription]] factor | ||
*Involved in cell cycle regulation | *Involved in [[Cell (biology)|cell]] cycle regulation | ||
*Interacts with histone deacetylases | *Interacts with [[histone]] deacetylases | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | 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> | *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;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Second most common translocation (after ''PML-RARA'') | *Second most common [[Translocations|translocation]] (after ''PML-[[RARA gene|RARA]]'') | ||
|- | |- | ||
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" | | | style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" | | ||
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5q35.1 | 5q35.1 | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Encodes nucleophosmin 1 (a nucleolar shuttle protein) | *Encodes nucleophosmin 1 (a nucleolar shuttle [[protein]]) | ||
*Involved in centromere duplication | *Involved in [[centromere]] duplication | ||
*Serves a protein chaperone | *Serves a [[protein]] [[chaperone]] | ||
*Regulates the cell cycle | *Regulates the [[Cell (biology)|cell]] cycle | ||
*Sequesters the tumor suppressor ''ARF'' in the nucleus and protects ''ARF'' from degradation | *Sequesters the tumor suppressor ''ARF'' in the [[nucleus]] and protects ''ARF'' from degradation | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | 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> | *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;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*''NPM1'' mutation carries a favorable prognosis in [[acute myeloid leukemia]] | *''[[NPM1 gene|NPM1]]'' [[mutation]] carries a favorable prognosis in [[acute myeloid leukemia]] | ||
*Rare translocation | *Rare [[Translocations|translocation]] | ||
|- | |- | ||
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11q13.4 | 11q13.4 | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Contributes to a structural component of the nuclear matrix | *Contributes to a structural component of the [[nuclear]] [[matrix]] | ||
*Interacts with microtubules | *Interacts with [[Microtubule|microtubules]] | ||
*Contributes to mitotic spindle formation during cell division | *Contributes to [[mitotic]] [[spindle]] formation during [[cell division]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | 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> | *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;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Rare translocation | *Rare [[Chromosomal translocation|translocation]] | ||
|- | |- | ||
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17q21.2 | 17q21.2 | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Encodes a signal transducer and activator of transcription (STAT) | *Encodes a signal transducer and activator of [[Transcription (genetics)|transcription]] ([[STAT]]) | ||
*Serves an intracellular transduction molecule for cytokine signaling | *Serves an [[intracellular]] [[transduction]] [[molecule]] for [[cytokine]] signaling | ||
*Translocates to the nucleus and functions as a transcription factor | *Translocates to the [[Cell nucleus|nucleus]] and functions as a [[Transcription (genetics)|transcription]] factor | ||
*Involved in T cell receptor signaling | *Involved in [[T cell]] [[Receptor (biochemistry)|receptor]] signaling | ||
*Involved in [[apoptosis]] | *Involved in [[apoptosis]] | ||
*Sequesters the tumor suppressor ''ARF'' in the nucleus and protects ''ARF'' from degradation | *Sequesters the [[tumor]] suppressor ''ARF'' in the [[nucleus]] and protects ''[[ARF]]'' from [[degradation]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | 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> | *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;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Rare translocation | *Rare [[Chromosomal translocation|translocation]] | ||
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Latest revision as of 16:14, 8 April 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]
Overview
The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene product 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
- The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.[1]
- 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. The translocation is designated as t(15;17)(q22;q12).[2][3]
- 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.[4][5]
- 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.[2]
- 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.[6]
| Translocation Partner | Chromosomal Location | Function | Response to Therapy | Other Features |
|---|---|---|---|---|
|
PML |
15q24.1 |
|
|
|
|
11q23.2 |
|
|
| |
|
NPM1 |
5q35.1 |
|
| |
|
NUMA[7] |
11q13.4 |
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|
|
STAT5B[8] |
17q21.2 |
|
|
|
References
- ↑ Zelent, Arthur; Guidez, Fabien; Melnick, Ari; Waxman, Samuel; Licht, Jonathan D (2001). "Translocations of the RARα gene in acute promyelocytic leukemia". Oncogene. 20 (49): 7186–7203. doi:10.1038/sj.onc.1204766. ISSN 0950-9232.
- ↑ 2.0 2.1 2.2 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.
- ↑ L. R. Hiorns, T. Min, G. J. Swansbury, A. Zelent, M. J. Dyer & D. Catovsky (1994). "Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17". Blood. 83 (10): 2946–2951. PMID 8180390. Unknown parameter
|month=ignored (help) - ↑ 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.
- ↑ "RARA retinoic acid receptor alpha [Homo sapiens (human)] - Gene - NCBI".
- ↑ Saeed, S; Logie, C; Stunnenberg, H G; Martens, J H A (2011). "Genome-wide functions of PML–RARα in acute promyelocytic leukaemia". British Journal of Cancer. 104 (4): 554–558. doi:10.1038/sj.bjc.6606095. ISSN 0007-0920.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 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.
- ↑ 8.0 8.1 8.2 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.