Ser/Thr Phosphatases: The New Frontier for Myeloid Leukemia Therapy?

Abstract

Myeloid leukemias are characterised by mutation and altered expression of a range of tyrosine kinases. Over 90% of chronic myeloid leukemias (CML) harbour the Philadelphia chromosome, resulting in expression of the BCR/ABL fusion protein, a constitutively active tyrosine kinase that is essential for survival of the CML cells. Acute myeloid leukemia (AML) is a heterogeneous disease characterised by mutations and dysregulation of a range of tyrosine kinases including the receptors Fms-like tyrosine kinase (Flt-3), c-KIT and platelet derived growth factor receptor (PDGFR). Tyrosine kinases represent powerful therapeutic targets, as the archetypical example of imatinib has shown for CML. However, many patients develop resistance to imatinib and other second generation inhibitors. Furthermore, trials of tyrosine kinase inhibitors for AML have thus far proven disappointing. Thus novel therapeutic targets are needed in order to improve the survival of myeloid leukemia patients. Oncogenic tyrosine kinases induce activation of a variety of signaling pathways required for the growth and survival of leukemia cells, such as the Ras/MAPK, PI3K/Akt, and JAK/STAT pathways. In addition to protein kinases, the rate and duration of protein phosphorylation is tightly regulated by the activity of protein phosphatases, and in normal cells the reversal of protein phosphorylation by phosphatases is essential for providing the fine-tuning of signaling pathways and maintaining a balance in cellular physiology. While much of the focus for targeted therapies in leukemia therapy has concentrated on the kinases responsible for phosphorylation events, relatively little attention has been given to the role that protein phosphatases play. However, research over the past decade has now begun to highlight the importance of protein phosphatases in leukemia and their potential as targets for novel therapies. In particular, the ser/thr phosphatase PP2A has emerged as an important tumor suppressor in myeloid leukemias and strategies aimed at reactivating this complex enzyme show great promise for a new generation of leukemia therapies