HAEM5:Chronic myeloid leukaemia: Difference between revisions

Approximately 50% of the patients who are diagnosed with CML are asymptomatic and diagnosed during the routine blood tests.<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> CML is a hematological disease that occurs predominantly in adults but in rare cases, it can occur in the pediatric population.<ref>{{Cite journal|last=Am|first=Mendizabal|last2=P|first2=Garcia-Gonzalez|last3=Ph|first3=Levine|date=2013|title=Regional Variations in Age at Diagnosis and Overall Survival Among Patients With Chronic Myeloid Leukemia From Low and Middle Income Countries|url=https://pubmed.ncbi.nlm.nih.gov/23411044/|language=en|pmid=23411044}}</ref> The onset of CML is insidious. Patients with CML usually experience dragging sensation of the abdomen due to splenomegaly. The clinical hallmark of CML is the uncontrolled proliferation of mature and maturing granulocytes at all stages of maturation: metamyelocytes, myelocytes, promyelocytes, and myeloblasts. Patients with CML usually begin with the initial chronic phase before entering the terminal blastic phase and 60-80% of the patients go through accelerated phase before reaching the terminal blastic phase. In chronic phase, CML patients show abnormal routine blood tests with clinical symptoms such as unintentional weight loss, loss of appetite, satiety, fatigue, insomnia and palpable splenomegaly. In rare cases, hyperviscosity syndrome can be a manifestation with a wide spectrum of features such as priapism, tinnitus, hearing loss, cerebral accidents and blindness. In the blastic phase, CML leukemic cells resemble acute leukemic cells morphologically. CNS and lymph node involvement are notable in the blastic phase of CML. If untreated, CML patients will progress to the terminal blastic phase in 3 to 5 years.   

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==Sites of Involvement==

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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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

'''Diagnosis:'''

Complete cytogenetic  response is defined as 0% of Philadelphia-chromosome (Ph)-positive cells in metaphase in bone marrow.<ref>{{Cite journal|last=J|first=Cortes|last2=A|first2=Quintás-Cardama|last3=Hm|first3=Kantarjian|date=2011|title=Monitoring Molecular Response in Chronic Myeloid Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/20960522/|language=en|doi=10.1002/cncr.25527|pmc=PMC4969001|pmid=20960522}}</ref>

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==Individual Region Genomic Gain / Loss / LOH==

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Not Applicable.

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==Characteristic Chromosomal Patterns==

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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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==Gene Mutations (SNV / INDEL)==

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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==Epigenomic Alterations==

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[[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>

[[File:9;22 image2K Abnormal Karyogram.jpg|thumb|Image courtesy of Fabiola Quintero-Rivera, MD]]

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==Genetic Diagnostic Testing Methods==