CML is distinguished from other myeloproliferative neoplasms by the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9. In about 95% of cases, the BCR-ABL gene is the product of a balanced (9;22) translocation that moves ABL from chromosome 9 to a position on chromosome 22 adjacent to BCR. In the remaining http://ebooksmedicine.net 5% of cases, a BCR-ABL fusion gene is created by cytogenetically cryptic or complex rearrangements involving more than two chromosomes. The BCR-ABL fusion gene is present in granulocytic, erythroid, megakaryocytic, and B cell precursors, and in some cases T cell precursors as well, indicating that the tumor arises from a transformed hematopoietic stem cell. Although the Ph chromosome is highly characteristic of CML, it also is present in 25% of adult B cell–ALLs and a small subset of AMLs.
As described in Chapter 6, the BCR-ABL gene encodes a fusion protein consisting of portions of BCR and the tyrosine kinase domain of ABL. Normal myeloid progenitors depend on signals generated by growth factors and their receptors for growth and survival. The growth factor dependence of CML progenitors is greatly decreased by constitutive signals generated by BCR-ABL that mimic the effects of growth factor receptor activation. Importantly, because BCR-ABL does not inhibit differentiation, the early disease course is marked by excessive production of relatively normal blood cells, particularly granulocytes and platelets.
MORPHOLOGYTheperipheralbloodfindingsarehighlycharacteristic.Theleukocytecountiselevated,oftenexceeding100,000cells/µL.
The circulating cells are predominantly neutrophils, metamyelocytes, and myelocytes (
Fig.12.28 ),butbasophils andeosinophils arealsoprominentandplateletsareusuallyincreased.Thebonemarrowishypercellularowingtoincreasednumbersofmaturinggranulocyticandmegakaryocyticprecursors.Theredpulpoftheenlargedspleenresemblesbonemarrowbecauseofthepresenceofextensiveextramedullary hematopoiesis. Thisburgeoningproliferationoftencompromisesthelocalbloodsupply,leadingtosplenic infarcts.
The onset of CML is insidious, as the initial symptoms usually are nonspecific (e.g., easy fatigability, weakness, weight loss). Sometimes the first symptom is a dragging sensation in the abdomen caused by splenomegaly. On occasion it may be necessary to distinguish CML from a lekemoid reaction a dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, and certain neoplasms. This distinction can be achieved definitively by testing for the presence of the BCR-ABL fusion gene, which can be done by karyotyping, fluorescence in situ hybridization, or PCR assay.
Fig. 12.28 CML—peripheralbloodsmear.Granulocyticformsatvariousstagesofdifferentiationarepresent.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)