Acute myeloid leukemia (AML) is a cancer of the bone marrow in which hyperproliferative blood cell progenitors are arrested in an early stage of development. Unfortunately, there is only a 20% cure rate for AML at 5 years post-diagnosis. Internal tandem duplications, the addition of several amino acids into the juxtamembrane domain of the FLT3 receptor (FLT3-ITDs), are found in approximately 30% of AML in both adults and children, and confer a poor prognosis. The protein tyrosine phosphatase, Shp2, is commonly overexpressed in AML, and we have previously found that it is constitutively associated with FLT3-ITD and that its genetic ablation reduces FLT3-ITD-stimulated cell hyperproliferation and STAT5 hyperactivation. Recently published studies from our lab suggest that a major site of Shp2 function is at FLT3-ITD tyrosine (Y) residue 599. However, the mechanism of how Shp2 works at FLT3-ITD to promote leukemogenesis is unknown. Based on the findings that both Src kinase and Syk kinase have been shown to interact with STAT5, that both kinases depend on Tyr599 for physical interaction with FLT3, and that Shp2 dephosphorylation of Src enhances its kinase activity, our over-riding hypothesis is that the duplicated Tyr599 on N51-FLT3-ITD permits increased Shp2 recruitment, allowing Shp2 to dephosphorylate, and thus activate Src, leading to Syk and STAT5 hyperactivation, thereby promoting leukemogenesis. To address this hypothesis, we will utilize FLT3-ITD constructs bearing mutation of Y599 to phenylalanine (F) and express dominant negative constructs of Shp2 phosphatase, Src kinase, and Lyn kinase to dissect the molecular mechanism linking Shp2 phosphatase activity with Syk kinase activity. Additionally, we will perform pre-clinical studies using pharmacologic inhibitors of Shp2 phosphatase and Syk kinase in primary AML cell proliferation assays in vitro and in a murine in vivo model of FLT3-ITD-induced leukemia. These studies are timely and innovative, as we will determine if inhibition of an activating tyrosine phosphatase (Shp2) cooperates with inhibition of activating tyrosine kinase (Syk), as a novel approach to therapy for AML.
Acute myeloid leukemia (AML) is a cancer of the bone marrow in which hyperproliferative blood cell progenitors are arrested in an early stage of development. Unfortunately, there is only a 20% cure rate for AML at 5 years post-diagnosis. The goals of the current project are to examine the cooperative role of Shp2 phosphatase with Syk kinase in promoting FLT3-ITD-stimulated STAT5 hyperphosphorylation and leukemogenesis.
| Richine, B M; Virts, E L; Bowling, J D et al. (2016) Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia. Leukemia 30:2094-2097 |
