Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content +++ BCR-ABL1-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA ++ BCR-ABL1–positive chronic myelogenous leukemia (CML) results from a somatic mutation in a pluripotential lymphohematopoietic cell, yielding a fusion oncogene (BCR-ABL1). CML is characterized by granulocytic leukocytosis, granulocytic immaturity, basophilia, anemia, and often thrombocytosis in the blood, intense leukemic granulocytic precursor expansion in the marrow, and splenomegaly. The natural history of the disease is to evolve into an accelerated phase in which cytopenias develop and response to chronic phase therapy is lost; either the chronic or accelerated phase can undergo further clonal evolution to acute leukemia. This natural history has been modified significantly by the introduction of inhibitors of the constitutive kinase activity of the BCR-ABL1 oncoprotein. +++ ETIOLOGY ++ Exposure to high-dose ionizing radiation increases the incidence of BCR-ABL1–positive CML, with a mode of increased incidence that ranges from 4 to 11 years in different exposed populations. Obesity may be an endogenous risk factor. +++ PATHOGENESIS +++ Genetic Abnormality ++ BCR-ABL1–positive CML is the result of an acquired genetic abnormality that induces a malignant transformation of a single pluripotential lymphohematopoietic cell. The proximate cause is a translocation between chromosome 9 and 22 [t(9;22)]. This alteration juxtaposes a portion of the ABL proto-oncogene from chromosome 9 to a portion of the BCR gene on chromosome 22. The resulting gene fusion, BCR-ABL1, creates an oncogene that encodes an elongated protein tyrosine phosphokinase (usually p210) that is constitutively expressed. This mutant protein disrupts cell signal pathways and results in the malignant transformation. The genetic alteration is present in erythroid, neutrophilic, eosinophilic, basophilic, monocytic, megakaryocytic, and marrow B- and T-lymphocytic cells, consistent with its origin in a pluripotential lymphohematopoietic cell. The designation Philadelphia (Ph) chromosome specifically refers to chromosome 22 with a shortened long arm (22q-) and is evident by light microscopy of cell metaphase preparations in approximately 90% of cases. Fluorescence in situ hybridization (FISH) can identify the fusion BCR-ABL1 gene in approximately 96% of cases. Approximately 4% of cases with a blood and marrow phenotype indistinguishable from BCR-ABL1 CML do not have rearrangement in the BCR gene. +++ Hematopoietic Abnormalities ++ There is a marked expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation resulting in an inexorable increase in white cell count and decrease in hemoglobin concentration. Megakaryocytopoiesis is often expanded. Erythropoiesis is usually moderately deficient. Function of the neutrophils and platelets is nearly normal; infection and bleeding are not a feature of the chronic phase. +++ EPIDEMIOLOGY ++ BCR-ABL1–positive CML accounts for approximately 15% of all cases of leukemia and approximately 3% of childhood leukemias in the United States. Males are affected at approximately 1.5 times the rate of females. The age-specific incidence rate increases exponentially from late adolescence (0.2 cases/100,000) to octogenarians (10 cases/100,000). Familial occurrence is ... Your Access profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'. Please click ‘Continue’ to continue the affiliation switch, otherwise click ‘Cancel’ to cancel signing in. Get Free Access Through Your Institution Learn how to see if your library subscribes to McGraw Hill Medical products. Subscribe: Institutional or Individual Sign In Username Error: Please enter User Name Password Error: Please enter Password Forgot Password? Forgot Username? Sign in via OpenAthens Sign in via Shibboleth You already have access! Please proceed to your institution's subscription. Create a free a profile for additional features.