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Updated: Jul 26, 2026
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
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.
Insights
Dedicator of cytokinesis 2 (DOCK2) interacts with FMS-like tyrosine kinase-3 (FLT3) in acute myeloid leukemia (AML). Inhibiting DOCK2 reduces leukemia cell growth and enhances sensitivity to AML treatments.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- FMS-like tyrosine kinase-3 (FLT3) mutations, particularly internal tandem duplications (ITDs), are common in acute myeloid leukemia (AML) and associated with poor prognosis.
- Targeting FLT3 effectively for long-term inhibition in AML remains a challenge.
- Understanding FLT3 interactions is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To identify proteins interacting with FLT3 using a mass spectrometry-based screen.
- To investigate the role of the identified protein, dedicator of cytokinesis 2 (DOCK2), in FLT3-mutated AML.
- To evaluate DOCK2 as a potential therapeutic target in AML.
Main Methods:
- Mass spectrometry-based screening to identify FLT3-interacting proteins.
- Expression analysis of DOCK2 in leukemia cell lines and primary AML samples.
- Co-immunoprecipitation assays to confirm FLT3-DOCK2 interaction.
- Short hairpin RNA (shRNA)-mediated knockdown (KD) of DOCK2.
- Cell proliferation and colony formation assays.
- In vivo studies using a mouse xenograft model.
Main Results:
- Dedicator of cytokinesis 2 (DOCK2), a guanine nucleotide exchange factor for Rho GTPases, was identified as an FLT3-interacting protein.
- DOCK2 is expressed in leukemia cells and co-immunoprecipitates with both wild-type FLT3 and FLT3/ITD.
- DOCK2 knockdown selectively inhibited proliferation and colony formation in leukemia cells with elevated FLT3 activity.
- DOCK2 knockdown sensitized these cells to cytarabine and FLT3 tyrosine kinase inhibitors.
- DOCK2 knockdown significantly prolonged survival in a mouse xenograft model of FLT3/ITD-positive leukemia.
Conclusions:
- DOCK2 plays a significant role in the survival of leukemia cells with elevated FLT3 activity.
- DOCK2 is a potential therapeutic target for novel AML treatments.
- Targeting DOCK2 can sensitize FLT3/ITD-positive leukemic cells to conventional chemotherapy and FLT3 inhibitors.
