Chronic myelogenous leukemia: from pathogenesis to therapy.

Abstract

CHRONIC MYELOGENOUS LEUKEMIA (CML) is a malignancy of the hematopoietic stem cell (HSC) (1) characterized by the Philadelphia chromosome (Ph) (2). The Ph is the result of a translocation between chromosomes 9 and 22, resulting in the formation of a hybrid BCR/ABL gene on chromosome 22 (3). The p210BCR/ABL oncoprotein is necessary and sufficient for transformation. Introduction of BCR/ABL into hematopoietic cell lines renders them cytokine independent in vitro and tumorigenic in vivo (4,5). Transplantation of BCR/ABL-transduced murine HSC causes a CML-like syndrome (6±8), and transgenic expression of BCR/ABL induces leukemias and lymphomas (9,10). Although these studies show the transforming potential of BCR/ABL, they do not explain the typical clinical features of CML. The clinical syndrome of CML can be summarized as an (a) abnormal, unregulated expansion of Ph1 progenitors and precursors (b) affecting the myeloid but not erythroid or lymphoid lineages, (c) which circulate prematurely in the peripheral blood and home to extramedullary locations and (d) demonstrate a tendency to acquire additional molecular defects, leading to blast crisis over a period of 3±5 years (11,12). In this article, we review the molecular pathways that are affected by the BCR/ABL oncoprotein and how this may explain the clinical features of the disease. We also discuss ongoing and future therapeutic approaches for CML that are based on our current understanding of the pathophysiology of CML.