DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells.

Abstract:

:The FMS-like tyrosine kinase-3 (FLT3) gene is the most commonly mutated gene in acute myeloid leukemia (AML), and patients carrying internal tandem duplication (ITD) mutations have a poor prognosis. Long-term inhibition of FLT3 activity in these patients has been elusive. To provide a more complete understanding of FLT3 biology, a mass spectroscopy-based screen was performed to search for FLT3-interacting proteins. The screen identified dedicator of cytokinesis 2 (DOCK2), which is a guanine nucleotide exchange factor for Rho GTPases, and its expression is limited to hematolymphoid cells. We show that DOCK2 is expressed in leukemia cell lines and primary AML samples, and DOCK2 co-immunoprecipitates with wild-type FLT3 and FLT3/ITD. Knockdown (KD) of DOCK2 by shRNA selectively reduced cell proliferation and colony formation in leukemia cell lines with increased FLT3 activity, and greatly sensitized these cells to cytarabine treatment, alone and in combination with FLT3 tyrosine kinase inhibitors. DOCK2 KD in an FLT3/ITD-positive leukemia cell line also significantly prolonged survival in a mouse xenograft model. These findings suggest that DOCK2 is a potential therapeutic target for novel AML treatments, as this protein regulates the survival of leukemia cells with elevated FLT3 activity and sensitizes FLT3/ITD leukemic cells to conventional antileukemic agents.

journal_name

Leukemia

journal_title

Leukemia

authors

Wu M,Hamaker M,Li L,Small D,Duffield AS

doi

10.1038/leu.2016.284

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

688-696

issue

3

eissn

0887-6924

issn

1476-5551

pii

leu2016284

journal_volume

31

pub_type

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