Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.
Ly P VuCamila PrietoElianna M AminSagar ChhangawalaAndrei KrivtsovM Nieves Calvo-VidalTimothy ChouArthur ChowGerard MinuesaSun Mi ParkTrevor S BarloweJames TaggartPatrick TivnanRaquel P DeeringLisa P ChuJeong-Ah KwonCem MeydanJavier Perales-PatónArora ArshiMithat GönenChristopher FamulareMinal PatelElisabeth PaiettaMartin S TallmanYuheng LuJacob Lowell GlassFrancine E Garret-BakelmanAri MelnickRoss LevineFatima Al-ShahrourMarcus JäråsNir HacohenAlexia HwangRalph GarippaChristopher J LengnerScott A ArmstrongLeandro CerchiettiGlenn S CowleyDavid RootJohn G DoenchChristina LeslieBenjamin L EbertMichael Gregory KharasPublished in: Nature genetics (2017)
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.
Keyphrases
- acute myeloid leukemia
- stem cells
- bone marrow
- cancer stem cells
- genome wide
- cell cycle arrest
- induced apoptosis
- genome wide identification
- dendritic cells
- long non coding rna
- endoplasmic reticulum stress
- cell death
- public health
- high throughput
- quality improvement
- transcription factor
- cell therapy
- signaling pathway
- pi k akt
- electronic health record
- big data
- cancer therapy
- drug delivery