Hematopoietic Lineage Involvement

CML is frequently referred to as a stem cell disease, since all three myeloid lineages (granulopoiesis, megakaryopoiesis, and erythropoiesis) carry the Ph chromosome. Data regarding the lymphoid cell compartment have been more conflicting, and there is apparently variation between different patients. In most patients, at least a proportion of the peripheral blood B cells are Ph positive.42 Mature T cells are usually Ph negative,43 while T-cell precursors were found to be positive in one study.44 The existence of myeloid and B-lymphoid (and in rare instances T-lymphoid) blastic transformation (see below), as well as the observation that endothelial cells may be Ph positive,45 is further support for the involvement of an early progenitor cell. There is still controversy as to whether Ph-positive ALL with a p210BCR-ABL fusion and lymphoid blast crisis are different entities or not.46 The fact that the hematopoiesis that recovers after intensive chemotherapy is usually Ph negative in the case of ALL but Ph positive in the case of lymphoid blast crisis argues for two distinct entities. The ability of interferon alpha,47 autologous stem cell transplantation,48 and, more impressively, imatinib5 to restore Ph-negative hematopoiesis in many patients indicates that normal hematopoietic progenitor cells survive in the presence of the CML cell clone. Remarkably, the most primitive stem cell compartment appears to be predominantly Ph negative in early phases of the disease, despite the fact that the peripheral myeloid cells are almost exclusively Ph positive.49 50 This has led to the notion that Bcr-Abl initially favors the expansion of committed progenitor cells (such as colony-forming units granulocyte-macrophage), while the stem cell compartment may be more resistant. Clearly, the question how the Bcr-Abl-positive cell clone outcompetes normal hematopoiesis is at the very heart of CML pathogenesis and is discussed in more detail further below.

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