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Updated: Aug 1, 2026
07:09
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Constitutively activated FLT3 phosphorylates BAD partially through pim-1
Kyu-Tae Kim1, Mark Levis, Donald Small
1Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
British Journal of Haematology
|July 28, 2006
Summary
Constitutively activating FLT3 mutations drive acute myeloid leukemia. Inhibiting FLT3 signaling reduces Bcl-2 antagonist of cell death (BAD) phosphorylation, a key survival mechanism, suggesting Pim-1 kinase is crucial for FLT3-mediated cell survival.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and associated with poor prognosis.
- FLT3 signaling pathways regulate cell survival and proliferation, making them attractive therapeutic targets.
Purpose of the Study:
- To investigate the role of anti- and proapoptotic proteins in FLT3 signaling.
- To identify key mediators of FLT3-driven cell survival, particularly the Bcl-2 antagonist of cell death (BAD).
Main Methods:
- Utilized BaF3/ITD and MV4-11 cell lines and primary AML samples.
- Administered FLT3 inhibitor CEP-701 to assess changes in protein phosphorylation.
- Employed siRNA to knockdown BAD expression.
- Analyzed phosphorylation of BAD at Ser-112 and Ser-136.
Main Results:
- FLT3 inhibition by CEP-701 led to decreased phosphorylation of BAD in cell lines and primary AML samples.
- BAD phosphorylation was rapidly reduced upon CEP-701 treatment.
- siRNA knockdown of BAD conferred resistance to CEP-701-induced apoptosis.
- Pim-1 kinase was identified as a principal kinase mediating FLT3/ITD signaling's anti-apoptotic function via BAD phosphorylation.
Conclusions:
- BAD phosphorylation is a critical downstream event in FLT3/ITD signaling, contributing to cell survival in AML.
- Pim-1 plays a significant role in mediating the anti-apoptotic effects of FLT3/ITD signaling through BAD phosphorylation.
- Targeting FLT3 and its downstream effectors like BAD presents a potential therapeutic strategy for AML.
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