Chronic myelogenous leukemia pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent bone marrow stem cells. The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q-. results in a ''BCR-ABL'' fusion gene and production of a BCR-ABL fusion protein. The gene product of the ''BCR-ABL'' gene constitutively activates numerous downstream targets including ''c-myc'', ''Akt'' and ''Jun'', all of which cause uncontrolled proliferation and survival of CML cells. | Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent bone marrow stem cells. The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q-. results in a ''BCR-ABL'' fusion gene and production of a BCR-ABL fusion protein. The gene product of the ''BCR-ABL'' gene constitutively activates numerous downstream targets including ''c-myc'', ''Akt'' and ''Jun'', all of which cause uncontrolled proliferation and survival of CML cells.<ref name="pmid26434969">{{cite journal |vauthors=Thompson PA, Kantarjian HM, Cortes JE |title=Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015 |journal=Mayo Clin. Proc. |volume=90 |issue=10 |pages=1440–54 |date=October 2015 |pmid=26434969 |pmc=5656269 |doi=10.1016/j.mayocp.2015.08.010 |url=}}</ref><ref name="pmid22054730">{{cite journal |vauthors=Jabbour E, Parikh SA, Kantarjian H, Cortes J |title=Chronic myeloid leukemia: mechanisms of resistance and treatment |journal=Hematol. Oncol. Clin. North Am. |volume=25 |issue=5 |pages=981–95, v |date=October 2011 |pmid=22054730 |pmc=4428141 |doi=10.1016/j.hoc.2011.09.004 |url=}}</ref> | ||
26434969/22054730 | |||
==Pathogenesis== | ==Pathogenesis== | ||
===Genetics=== | ===Genetics=== | ||
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the occurrence of the Philadelphia chromosome which is thought to be a definitive diagnostic marker for CML. In [[Philadelphia chromosome]] translocation, parts of two chromosomes (the 9<sup>th</sup> and 22<sup>nd</sup> by conventional [[karyotype|karyotypic]] numbering) switch places. As a result, part of the ''BCR'' ("breakpoint cluster region") gene from chromosome 22 is fused with the ''ABL (''"abelson murine leukemia"'')'' gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because ''[[ABL]]'' carries a domain that can add phosphate groups to tyrosine residues (a [[tyrosine kinase]]), the ''[[BCR]]-[[ABL]]'' fusion gene product is also a tyrosine kinase. The fused ''[[BCR]]-[[ABL]]'' protein interacts with the interleukin 3beta c receptor subunit. The ''[[BCR]]-[[ABL]]'' transcript is continuously active and does not require activation by other cellular messaging proteins that promotes growth and replication through downstream pathways such as RAS, RAF, JUN kinase, MYC, and STAT. In turn ''[[BCR]]-[[ABL]]'' activates a cascade of proteins which control the [[cell cycle]], speeding up cell division. Moreover the ''[[BCR]]-[[ABL]]'' protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the ''[[BCR]]-[[ABL]]'' protein is the pathophysiologic cause of chronic myelogenous leukemia.<ref name="Hehlmann">{{cite journal|title=Chronic myeloid leukaemia|author=Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet|journal=Lancet|volume=370|issue=9584|pages=342-50|date=2007|pmid=17662883}}</ref>. | Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the occurrence of the Philadelphia chromosome which is thought to be a definitive diagnostic marker for CML. In [[Philadelphia chromosome]] translocation, parts of two chromosomes (the 9<sup>th</sup> and 22<sup>nd</sup> by conventional [[karyotype|karyotypic]] numbering) switch places. As a result, part of the ''BCR'' ("breakpoint cluster region") gene from chromosome 22 is fused with the ''ABL (''"abelson murine leukemia"'')'' gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because ''[[ABL]]'' carries a domain that can add phosphate groups to tyrosine residues (a [[tyrosine kinase]]), the ''[[BCR]]-[[ABL]]'' fusion gene product is also a tyrosine kinase. The fused ''[[BCR]]-[[ABL]]'' protein interacts with the interleukin 3beta c receptor subunit. The ''[[BCR]]-[[ABL]]'' transcript is continuously active and does not require activation by other cellular messaging proteins that promotes growth and replication through downstream pathways such as RAS, RAF, JUN kinase, MYC, and STAT. In turn ''[[BCR]]-[[ABL]]'' activates a cascade of proteins which control the [[cell cycle]], speeding up cell division. Moreover the ''[[BCR]]-[[ABL]]'' protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the ''[[BCR]]-[[ABL]]'' protein is the pathophysiologic cause of chronic myelogenous leukemia.<ref name="Hehlmann">{{cite journal|title=Chronic myeloid leukaemia|author=Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet|journal=Lancet|volume=370|issue=9584|pages=342-50|date=2007|pmid=17662883}}</ref>.<ref name="pmid24729196">{{cite journal |vauthors=Jabbour E, Kantarjian H |title=Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management |journal=Am. J. Hematol. |volume=89 |issue=5 |pages=547–56 |date=May 2014 |pmid=24729196 |doi=10.1002/ajh.23691 |url=}}</ref><ref name="pmid26434969">{{cite journal |vauthors=Thompson PA, Kantarjian HM, Cortes JE |title=Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015 |journal=Mayo Clin. Proc. |volume=90 |issue=10 |pages=1440–54 |date=October 2015 |pmid=26434969 |pmc=5656269 |doi=10.1016/j.mayocp.2015.08.010 |url=}}</ref><ref name="pmid26625737">{{cite journal |vauthors=Kaleem B, Shahab S, Ahmed N, Shamsi TS |title=Chronic Myeloid Leukemia--Prognostic Value of Mutations |journal=Asian Pac. J. Cancer Prev. |volume=16 |issue=17 |pages=7415–23 |date=2015 |pmid=26625737 |doi= |url=}}</ref> | ||
==References== | ==References== | ||
Revision as of 14:27, 31 July 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]
Overview
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent bone marrow stem cells. The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal t(9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q-. results in a BCR-ABL fusion gene and production of a BCR-ABL fusion protein. The gene product of the BCR-ABL gene constitutively activates numerous downstream targets including c-myc, Akt and Jun, all of which cause uncontrolled proliferation and survival of CML cells.[1][2]
Pathogenesis
Genetics
Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the occurrence of the Philadelphia chromosome which is thought to be a definitive diagnostic marker for CML. In Philadelphia chromosome translocation, parts of two chromosomes (the 9th and 22nd by conventional karyotypic numbering) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL ("abelson murine leukemia") gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because ABL carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the BCR-ABL fusion gene product is also a tyrosine kinase. The fused BCR-ABL protein interacts with the interleukin 3beta c receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins that promotes growth and replication through downstream pathways such as RAS, RAF, JUN kinase, MYC, and STAT. In turn BCR-ABL activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia.[3].[4][1][5]
References
- ↑ 1.0 1.1 Thompson PA, Kantarjian HM, Cortes JE (October 2015). "Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015". Mayo Clin. Proc. 90 (10): 1440–54. doi:10.1016/j.mayocp.2015.08.010. PMC 5656269. PMID 26434969.
- ↑ Jabbour E, Parikh SA, Kantarjian H, Cortes J (October 2011). "Chronic myeloid leukemia: mechanisms of resistance and treatment". Hematol. Oncol. Clin. North Am. 25 (5): 981–95, v. doi:10.1016/j.hoc.2011.09.004. PMC 4428141. PMID 22054730.
- ↑ Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet (2007). "Chronic myeloid leukaemia". Lancet. 370 (9584): 342–50. PMID 17662883.
- ↑ Jabbour E, Kantarjian H (May 2014). "Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management". Am. J. Hematol. 89 (5): 547–56. doi:10.1002/ajh.23691. PMID 24729196.
- ↑ Kaleem B, Shahab S, Ahmed N, Shamsi TS (2015). "Chronic Myeloid Leukemia--Prognostic Value of Mutations". Asian Pac. J. Cancer Prev. 16 (17): 7415–23. PMID 26625737.