Signal transduction in the chronic leukemias: implications for targeted therapies

Abstract

The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways.

Figure 1. BCR-ABL1-induced signaling pathways in CML

Schematic representation of the myriad signaling pathways that are activated in CML cells. Phosphorylation is represented by red “P” symbols. Arrowheads indicate activation of a downstream molecule, while a bar at the end of a line indicates inhibition of a downstream molecule. (Adapted from Goldman and Melo, N. Eng. J. Med 2003;349:1451).