Targeting Aberrant Signaling in Myeloid Malignancies: Promise Versus Reality

Abstract

Clonal myeloid disorders are characterized by genetic alterations that activate cytokine signaling pathways and stimulate cell proliferation. These activated signaling pathways have been extensively studied as potential therapeutic targets, and tyrosine kinase inhibitors have indeed had extraordinary success in treating BCR/ABL-positive chronic myeloiud leukemia. However, although inhibitors of other activated kinases have been developed that perform well in preclinical studies, the therapeutic efficacy of these drugs in patients has been unimpressive. This article discusses potential reasons for these discordant results and outlines recent scientific advances that are informing future efforts to target activated kinases in clonal myeloid disorders.

Keywords: Acute myeloid leukemia; BCR-ABL; Calreticulin; FLT3; JAK2; Myeloproliferative neoplasms; Oncogene addiction; Tyrosine kinase inhibitor.