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Published on: November 18, 2009
Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells
Ly P Vu1, Camila Prieto1,2, Elianna M Amin1
1Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, and Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Abstract:
The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.
Insights
Scientists identified Syncrip (SYNCRIP) as a key RNA-binding protein regulating myeloid leukemia stem cells. Depleting SYNCRIP halts cancer progression, offering a potential new therapeutic target for leukemia.
Area of Science:
- Molecular Biology
- Oncology
- Hematology
Background:
- The RNA-binding proteins (RBPs) controlling cancer stem cells are not well understood.
- MSI2 RBP is a key regulator of cancer stem cell translation.
- Identifying novel RBPs is crucial for understanding leukemia stem cell biology.
Purpose of the Study:
- To identify novel RNA-binding proteins (RBPs) involved in regulating cancer stem cells, specifically in myeloid leukemia.
- To elucidate the role of the RNA-binding protein Syncrip (SYNCRIP) in leukemogenesis and its interaction with known regulators like MSI2 and HOXA9.
Main Methods:
- Proteomic analysis of the MSI2-interacting RBP network.
- Functional shRNA screening to identify essential genes in vivo.
- Gene expression profiling of SYNCRIP-depleted leukemia cells.
Main Results:
- Identified 24 genes crucial for in vivo leukemia, with SYNCRIP being highly differentially required in myeloid leukemia cells.
- SYNCRIP depletion led to increased apoptosis and differentiation, delaying leukemogenesis.
- SYNCRIP maintains HOXA9 translation, a critical component of the leukemia stem cell program; MSI2 or HOXA9 overexpression rescued SYNCRIP depletion effects.
Conclusions:
- SYNCRIP is a novel RNA-binding protein that regulates the myeloid leukemia stem cell program.
- Targeting SYNCRIP and its associated RBP complexes presents a potential therapeutic strategy for leukemia.
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