title: 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.
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hamaker
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Small
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001773:Blood Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D020690:GTPase-Activating Proteins; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; D051941:fms-Like Tyrosine Kinase 3; D020830:rac1 GTP-Binding Protein