HAEM5:Chronic myeloid leukaemia: Difference between revisions
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{{DISPLAYTITLE:Chronic myeloid leukaemia}} | {{DISPLAYTITLE:Chronic myeloid leukaemia}} | ||
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | ||
{{Under Construction}} | {{Under Construction}} | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Chronic Myeloid Leukemia (CML), BCR-ABL1 Positive]]. | ||
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|Subtype(s) | |Subtype(s) | ||
|Chronic myeloid leukaemia | |Chronic myeloid leukaemia | ||
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<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
CML is the first cancer that is known to be linked to a specific genetic abnormality, namely the balanced chromosomal translocation known as Philadelphia Chromosome. A focal gene area of BCR (Breakpoint Cluster Region) from chromosome 22 is fused with another gene ABL (Tyrosine protein kinase ABL) that is located on chromosome 9. The chimeric oncogene BCR-ABL is the central to the pathology of CML because ABL carries a domain that is capable of phosphorylating tyrosine residues, activating a cascade of proteins that control the cell cycle. It was reported that 90% - 95% of the CML in chronic phase shows characteristic t(9;22)(q34;q11.2) reciprocal translocation that results in the Ph chromosome. This balanced translocation leads to the formation of the ''BCR/ABL'' fusion gene on chromosome 22 and a reciprocal ''ABL/BCR'' fusion gene on chromosome 9. Studies has shown that the latter gene ''ABL/BCR'' fusion gene does not seem to have any crucial role in CML and no ABL/BCR protein has been found. | CML is the first cancer that is known to be linked to a specific genetic abnormality, namely the balanced chromosomal translocation known as Philadelphia Chromosome. A focal gene area of BCR (Breakpoint Cluster Region) from chromosome 22 is fused with another gene ABL (Tyrosine protein kinase ABL) that is located on chromosome 9. The chimeric oncogene BCR-ABL is the central to the pathology of CML because ABL carries a domain that is capable of phosphorylating tyrosine residues, activating a cascade of proteins that control the cell cycle. It was reported that 90% - 95% of the CML in chronic phase shows characteristic t(9;22)(q34;q11.2) reciprocal translocation that results in the Ph chromosome. This balanced translocation leads to the formation of the ''BCR/ABL'' fusion gene on chromosome 22 and a reciprocal ''ABL/BCR'' fusion gene on chromosome 9. Studies has shown that the latter gene ''ABL/BCR'' fusion gene does not seem to have any crucial role in CML and no ABL/BCR protein has been found. | ||
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<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in: | ||
* Chromosomal Rearrangements (Gene Fusions) | * Chromosomal Rearrangements (Gene Fusions) | ||
* Individual Region Genomic Gain/Loss/LOH | * Individual Region Genomic Gain/Loss/LOH | ||
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<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
Not Applicable. | Not Applicable. | ||
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<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
Atypical chronic myeloid leukemia (aCML) is a subtype of myelodysplastic/myeloproliferative neoplasm that lacks Philadelphia chromosome or rearrangements of PDGFRA, PDGFRB, or FGFR1. This hematological disorder has a considerable overlapping clinicopathological features with CML and CMML. It differs from CML by older median age, lower level of granulocytosis, multilineage dysplasia and lack of basophilia. Up until now, no cytogenetic changes have been associated with aCML. In peripheral blood smear, aCML typically shows granulocytic leukocytosis with striking neutrophil dysplasia (nuclear hyposegmentation and hypogranularity). | Atypical chronic myeloid leukemia (aCML) is a subtype of myelodysplastic/myeloproliferative neoplasm that lacks Philadelphia chromosome or rearrangements of PDGFRA, PDGFRB, or FGFR1. This hematological disorder has a considerable overlapping clinicopathological features with CML and CMML. It differs from CML by older median age, lower level of granulocytosis, multilineage dysplasia and lack of basophilia. Up until now, no cytogenetic changes have been associated with aCML. In peripheral blood smear, aCML typically shows granulocytic leukocytosis with striking neutrophil dysplasia (nuclear hyposegmentation and hypogranularity). | ||
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|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content. | |}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content. | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
A few genes were noted to be altered during the transformed stages of CML, namely TP53'', RB1, MYC, CDKN2A, NRAS, KRAS, RUNX1, MECOM, TET2, CBL, ASXL1, IDH1'' and ''IDH2''. | A few genes were noted to be altered during the transformed stages of CML, namely TP53'', RB1, MYC, CDKN2A, NRAS, KRAS, RUNX1, MECOM, TET2, CBL, ASXL1, IDH1'' and ''IDH2''. | ||
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<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
[[File:BCR-ABL-ASS1 abnormal double fusions.jpg|thumb|Image courtesy of Fabiola Quintero-Rivera, MD]] | [[File:BCR-ABL-ASS1 abnormal double fusions.jpg|thumb|Image courtesy of Fabiola Quintero-Rivera, MD]] | ||
Breakpoint Cluster Region protein (BCR) is encoded by ''BCR'' gene, located on chromosome 22. BCR protein has serine/threonine kinase activity.<ref name=":0" /> The protein is also a GTPase-activating protein for p21rac and other kinases.<ref>{{Cite journal|title=BCR BCR activator of RhoGEF and GTPase [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=613}}</ref> BCR protein is involved in the two main pathways: FGFR1 mutant receptor activation and G-protein signaling HRAS regulation pathway.<ref>{{Cite journal|last=Mn|first=Peiris|last2=F|first2=Li|last3=Dj|first3=Donoghue|date=2019|title=BCR: A Promiscuous Fusion Partner in Hematopoietic Disorders|url=https://pubmed.ncbi.nlm.nih.gov/31105873/|language=en|doi=10.18632/oncotarget.26837|pmc=PMC6505627|pmid=31105873}}</ref> BCR-associated genetic rearrangement gives rise to hematological disorders. The ''ABL1'' gene is located on chromosome 9q34.12 and encodes for ABL1 protein, which was discovered to be a tyrosine kinase protein.<ref>{{Cite journal|last=B|first=Chereda|last2=Jv|first2=Melo|date=2015|title=Natural Course and Biology of CML|url=https://pubmed.ncbi.nlm.nih.gov/25814077/|language=en|pmid=25814077}}</ref> Depending on the breakpoint of the ''BCR'' gene, the size of the fusion protein can vary: p190bcr-abl, p210bcr-abl, and p230bcr-abl, leading to three different isoforms.<ref name=":0" /> ''BCR-ABL1'' gene fusion encodes a chimeric protein, which is mostly 210 kDa(P210''BCRABL1'') with constitutive tyrosine-kinase activity, escaping the cytokine regulation and regulatory controls of many intracellular signaling pathways that are associated with proliferation, differentiation and apoptosis.<ref>{{Cite journal|last=Jb|first=Konopka|last2=Sm|first2=Watanabe|last3=On|first3=Witte|date=1984|title=An Alteration of the Human C-Abl Protein in K562 Leukemia Cells Unmasks Associated Tyrosine Kinase Activity|url=https://pubmed.ncbi.nlm.nih.gov/6204766/|language=en|pmid=6204766}}</ref><ref>{{Cite journal|last=R|first=Ren|date=2005|title=Mechanisms of BCR-ABL in the Pathogenesis of Chronic Myelogenous Leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/15719031/|language=en|pmid=15719031}}</ref> Many of the target proteins that are affected by dimerization of constitutive kinase activity of BCR-ABL fusion protein include STAT, RAS, RAF, JUN kinase, MYC, AKT, and other transducers.<ref>{{Cite journal|last=S|first=Faderl|last2=M|first2=Talpaz|last3=Z|first3=Estrov|last4=S|first4=O'Brien|last5=R|first5=Kurzrock|last6=Hm|first6=Kantarjian|date=1999|title=The Biology of Chronic Myeloid Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10403855/|language=en|pmid=10403855}}</ref><ref>{{Cite journal|last=Cl|first=Sawyers|date=1999|title=Chronic Myeloid Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10219069/|language=en|pmid=10219069}}</ref> It was shown that when CML progresses to the blastic crisis phase, a new additional mutation is acquired GSK3beta, which leads to the activation of beta-catenin, preventing myeloid cell lineages to mature.<ref>{{Cite journal|last=Ch|first=Jamieson|last2=Le|first2=Ailles|last3=Sj|first3=Dylla|last4=M|first4=Muijtjens|last5=C|first5=Jones|last6=Jl|first6=Zehnder|last7=J|first7=Gotlib|last8=K|first8=Li|last9=Mg|first9=Manz|date=2004|title=Granulocyte-macrophage Progenitors as Candidate Leukemic Stem Cells in Blast-Crisis CML|url=https://pubmed.ncbi.nlm.nih.gov/15306667/|language=en|pmid=15306667}}</ref><ref>{{Cite journal|last=Ae|first=Abrahamsson|last2=I|first2=Geron|last3=J|first3=Gotlib|last4=Kh|first4=Dao|last5=Cf|first5=Barroga|last6=Ig|first6=Newton|last7=Fj|first7=Giles|last8=J|first8=Durocher|last9=Rs|first9=Creusot|date=2009|title=Glycogen Synthase Kinase 3beta Missplicing Contributes to Leukemia Stem Cell Generation|url=https://pubmed.ncbi.nlm.nih.gov/19237556/|language=en|doi=10.1073/pnas.0900189106|pmc=PMC2646624|pmid=19237556}}</ref> | Breakpoint Cluster Region protein (BCR) is encoded by ''BCR'' gene, located on chromosome 22. BCR protein has serine/threonine kinase activity.<ref name=":0">Silver RT. Molecular Biology of CML. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK13554/</nowiki></ref> The protein is also a GTPase-activating protein for p21rac and other kinases.<ref>{{Cite journal|title=BCR BCR activator of RhoGEF and GTPase [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=613}}</ref> BCR protein is involved in the two main pathways: FGFR1 mutant receptor activation and G-protein signaling HRAS regulation pathway.<ref>{{Cite journal|last=Mn|first=Peiris|last2=F|first2=Li|last3=Dj|first3=Donoghue|date=2019|title=BCR: A Promiscuous Fusion Partner in Hematopoietic Disorders|url=https://pubmed.ncbi.nlm.nih.gov/31105873/|language=en|doi=10.18632/oncotarget.26837|pmc=PMC6505627|pmid=31105873}}</ref> BCR-associated genetic rearrangement gives rise to hematological disorders. The ''ABL1'' gene is located on chromosome 9q34.12 and encodes for ABL1 protein, which was discovered to be a tyrosine kinase protein.<ref>{{Cite journal|last=B|first=Chereda|last2=Jv|first2=Melo|date=2015|title=Natural Course and Biology of CML|url=https://pubmed.ncbi.nlm.nih.gov/25814077/|language=en|pmid=25814077}}</ref> Depending on the breakpoint of the ''BCR'' gene, the size of the fusion protein can vary: p190bcr-abl, p210bcr-abl, and p230bcr-abl, leading to three different isoforms.<ref name=":0" /> ''BCR-ABL1'' gene fusion encodes a chimeric protein, which is mostly 210 kDa(P210''BCRABL1'') with constitutive tyrosine-kinase activity, escaping the cytokine regulation and regulatory controls of many intracellular signaling pathways that are associated with proliferation, differentiation and apoptosis.<ref>{{Cite journal|last=Jb|first=Konopka|last2=Sm|first2=Watanabe|last3=On|first3=Witte|date=1984|title=An Alteration of the Human C-Abl Protein in K562 Leukemia Cells Unmasks Associated Tyrosine Kinase Activity|url=https://pubmed.ncbi.nlm.nih.gov/6204766/|language=en|pmid=6204766}}</ref><ref>{{Cite journal|last=R|first=Ren|date=2005|title=Mechanisms of BCR-ABL in the Pathogenesis of Chronic Myelogenous Leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/15719031/|language=en|pmid=15719031}}</ref> Many of the target proteins that are affected by dimerization of constitutive kinase activity of BCR-ABL fusion protein include STAT, RAS, RAF, JUN kinase, MYC, AKT, and other transducers.<ref>{{Cite journal|last=S|first=Faderl|last2=M|first2=Talpaz|last3=Z|first3=Estrov|last4=S|first4=O'Brien|last5=R|first5=Kurzrock|last6=Hm|first6=Kantarjian|date=1999|title=The Biology of Chronic Myeloid Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10403855/|language=en|pmid=10403855}}</ref><ref>{{Cite journal|last=Cl|first=Sawyers|date=1999|title=Chronic Myeloid Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10219069/|language=en|pmid=10219069}}</ref> It was shown that when CML progresses to the blastic crisis phase, a new additional mutation is acquired GSK3beta, which leads to the activation of beta-catenin, preventing myeloid cell lineages to mature.<ref>{{Cite journal|last=Ch|first=Jamieson|last2=Le|first2=Ailles|last3=Sj|first3=Dylla|last4=M|first4=Muijtjens|last5=C|first5=Jones|last6=Jl|first6=Zehnder|last7=J|first7=Gotlib|last8=K|first8=Li|last9=Mg|first9=Manz|date=2004|title=Granulocyte-macrophage Progenitors as Candidate Leukemic Stem Cells in Blast-Crisis CML|url=https://pubmed.ncbi.nlm.nih.gov/15306667/|language=en|pmid=15306667}}</ref><ref>{{Cite journal|last=Ae|first=Abrahamsson|last2=I|first2=Geron|last3=J|first3=Gotlib|last4=Kh|first4=Dao|last5=Cf|first5=Barroga|last6=Ig|first6=Newton|last7=Fj|first7=Giles|last8=J|first8=Durocher|last9=Rs|first9=Creusot|date=2009|title=Glycogen Synthase Kinase 3beta Missplicing Contributes to Leukemia Stem Cell Generation|url=https://pubmed.ncbi.nlm.nih.gov/19237556/|language=en|doi=10.1073/pnas.0900189106|pmc=PMC2646624|pmid=19237556}}</ref> | ||
[[File:9;22 image2K Abnormal Karyogram.jpg|thumb|Image courtesy of Fabiola Quintero-Rivera, MD]] | [[File:9;22 image2K Abnormal Karyogram.jpg|thumb|Image courtesy of Fabiola Quintero-Rivera, MD]] | ||
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==Notes== | ==Notes== | ||
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<nowiki>*</nowiki>''Citation of this Page'': “Chronic myeloid leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Chronic_myeloid_leukaemia</nowiki>. | <nowiki>*</nowiki>''Citation of this Page'': “Chronic myeloid leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Chronic_myeloid_leukaemia</nowiki>. | ||
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases C]] | [[Category:HAEM5]] | ||
[[Category:DISEASE]] | |||
[[Category:Diseases C]] | |||