Abstract

The type III receptor tyrosine kinase FLT3 is one of the most commonly mutated oncogenes in acute myeloid leukemia (AML). Inhibition of mutated FLT3 in combination with chemotherapy has displayed promising results in clinical trials. However, one of the major obstacles in targeting FLT3 is the development of resistant disease due to secondary mutations in FLT3 that lead to relapse. FLT3 and its oncogenic mutants signal through associating proteins that activate downstream signaling. Thus, targeting proteins that interact with FLT3 and their downstream signaling cascades can be an alternative approach to treat FLT3-dependent AML. We used an SH2 domain array screen to identify novel FLT3 interacting proteins and identified ABL2 as a potent interacting partner of FLT3. To understand the role of ABL2 in FLT3-mediated biological and cellular events, we used the murine pro-B cell line Ba/F3 as a model system. Overexpression of ABL2 in Ba/F3 cells expressing an oncogenic mutant of FLT3 (FLT3-ITD) resulted in partial inhibition of FLT3-ITD-dependent cell proliferation and colony formation. ABL2 expression did not alter the kinase activity of FLT3, its ubiquitination or its stability. However, it partially blocked FLT3-induced AKT phosphorylation without affecting ERK1/2 and p38 activation. Taken together our data suggest that ABL2 acts as negative regulator of signaling downstream of FLT3.

Highlights

  • The mammalian genome encodes more than 500 protein kinases that contribute to the regulation of almost all cellular events

  • Identification of ABL2 as a FLT3 binding protein. Receptor tyrosine kinases such as FLT3 signal through proteins that associate with the activated receptor

  • Three different tyrosine phosphorylated peptides corresponding to residues Y726, Y793 and Y842 in FLT3 were used to determine the binding to the SH2 domains

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Summary

Introduction

The mammalian genome encodes more than 500 protein kinases that contribute to the regulation of almost all cellular events. The type III receptor tyrosine kinase family includes the receptors for platelet derived growth factors (PDGFRA and PDGFRB), the receptor for stem cell factor (SCFR or KIT), FMS-like tyrosine kinase 3 (FLT3, the receptor for FLT3 ligand, FL) and the colony-stimulating factor 1 receptor (CSF1R). Several members of this family are important regulators of the hematopoietic system and have been implicated in various hematological malignancies including acute myeloid leukemia (AML). The adaptor proteins GRB10 [5] and GADS [6], and the non-receptor tyrosine kinases SYK [7] and FYN [8], enhance downstream signaling

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