Cytogenetic and molecular aspects of cml

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The discovery of the Philadelphia chromosome in 1960, its subsequent characterization as a 9;22 translocation in 1973, and the cloning of the BCR and ABL1 genes that fuse as a result of the translocation, opened the field of genomic medicine. Building on these seminal discoveries, researchers developed drugs targeted at specific regions of the abnormal protein product of this chimeric BCR-ABL1 gene, thus beginning the era of targeted therapy and personalized medicine. The 9;22 translocation characteristic of chronic myeloid leukemia (CML) fuses ABL1 at 9q34 with BCR at 22q11.2, resulting in a chimeric gene that encodes an abnormal fusion protein. This BCR-ABL1 protein has a constitutively active tyrosine kinase domain that causes uncontrolled cell proliferation, ultimately leading to the clinicopathologic features of CML. Because this gene fusion occurs in an early hematopoietic stem cell, all hematopoietic cell lines are affected, and blast phase can present as an acute lymphoblastic as well as acute myeloid leukemia. Because the BCR-ABL1 gene fusion is the sine qua non of CML, cytogenetic and molecular testing are invaluable tools in the evaluation and monitoring of CML. These techniques include conventional cytogenetic analysis using chromosome banding, molecular cytogenetic techniques (e.g., fluorescence in situ hybridization [FISH]), and the polymerase chain reaction (PCR). Conventional cytogenetic analysis characterizes the type of translocation (simple or complex) and documents the presence or absence of additional chromosomal abnormalities. Molecular cytogenetic techniques can confirm the presence of a BCR-ABL1 fusion in interphase (nondividing) cells, and additionally can document submicroscopic deletions on the derivative chromosome 9, which occur in approximately 15% of cases of t(9;22). Conventional cytogenetic analysis can also identify clonal abnormalities arising in Philadelphia chromosome-negative cells in patients receiving tyrosine kinase inhibitor (TKI) therapy. The widespread use and success of TKI therapy necessitated the development of testing methods sufficiently sensitive to assess continually decreasing levels of disease. Quantitative real-time reverse transcriptase-PCR (qRT-PCR) technology provides the means to define specific therapeutic goals and to follow BCR-ABL1 transcript levels over time. Such monitoring is critical for early recognition of TKI resistance, as well as for identification of the mutations underlying such resistance. Cytogenetic and molecular diagnostic laboratories thus play an integral role in the care of patients with CML, from initial diagnosis to minimal residual disease (MRD) testing and assessment of therapeutic resistance. Advances such as array-based comparative genomic hybridization and next-generation sequencing promise to elucidate further the pathophysiology of this disease.

Original languageEnglish (US)
Title of host publicationChronic Myeloid Leukemia
Subtitle of host publicationFrom Daily Management to Complicated Issues
PublisherNova Science Publishers, Inc.
Number of pages30
ISBN (Electronic)9781629489926
ISBN (Print)9781629489711
StatePublished - Jan 1 2014


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