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Bone Marrow Mesenchymal Stromal Cells Support Translation in Refractory Acute Myeloid Leukemia

ABSTRACT: In acute myeloid leukemia (AML), malignant cells surviving chemotherapy rely on high mRNA translation and their microenvironmental metabolic support to drive relapse. However, the role of translational reprogramming in the niche is unclear. Here we found that relapsing AML cells increase translation in their bone marrow (BM) niches, where BM mesenchymal stromal cells (BMSCs) become a source of eIF4A-cap-dependent translation machinery that is transferred to AML cells via extracellular vesicles (EVs), to meet their translational demands. In two independent models of highly chemo-resistant AML driven by MLL-AF9 or FLT3-ITD;NPMc mutations, protein synthesis levels increase in refractory AML dependently on nestin+ BMSCs. Inhibiting cap-dependent translation in BMSCs abolishes their chemoprotective ability, while EVs from BMSCs carrying eIF4A boost AML cell translation and survival. Consequently, eIF4A inhibition synergizes with conventional chemotherapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Blood Cell, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: Simon Mendez Ferrer

LAB HEAD: Simon Mendez Ferrer

PROVIDER: PXD058646 | Pride | 2024-12-27

REPOSITORIES: Pride

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			Action	DRS
	P1045_051121_ClickIT_AHA_2.Scaffold.mzid.gz_P1045_1_Blasts_No_AHA_F014627.MGF	Mzid
	P1045_051121_ClickIT_AHA_2.Scaffold.mzid.gz_P1045_2_Blasts_AHA_F014628.MGF	Mzid
	P1045_051121_ClickIT_AHA_2.Scaffold.mzid.gz_P1045_2_Blasts_AHA_plus_chemo_F014629.MGF	Mzid
	P1045_1_Blasts_No_AHA.mgf	Mgf
	P1045_2_Blasts_AHA.mgf	Mgf

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Project description:DEAD-box RNA helicases eIF4A and Ded1 are believed to promote translation initiation by resolving mRNA secondary structures that impede ribosome attachment at the mRNA 5’ end or subsequent scanning of the 5’UTR, but whether they perform distinct functions or act redundantly in vivo is poorly understood. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling. Despite similar reductions in bulk translation, inactivation of a cold-sensitive Ded1 mutant substantially reduced the TEs of >600 mRNAs, whereas inactivation of a temperature-sensitive eIF4A mutant yielded <40 similarly impaired mRNAs. The broader requirement for Ded1 did not reflect more pervasive secondary structures at low temperature, as inactivation of temperature-sensitive and cold-sensitive ded1 mutants gave highly correlated results. Interestingly, Ded1-dependent mRNAs exhibit greater than average 5’UTR length and propensity for secondary structure, implicating Ded1 in scanning though structured 5' UTRs. Reporter assays confirmed that cap- distal stem-loop insertions increase dependence on Ded1 but not eIF4A for efficient translation. While only a small fraction of mRNAs is strongly dependent on eIF4A, this dependence is significantly correlated with requirements for Ded1 and 5’UTR features characteristic of Ded1- dependent mRNAs. Our findings suggest that Ded1 is critically required to promote scanning through secondary structures within 5’UTRs; and while eIF4A cooperates with Ded1 in this function, it also promotes a step of initiation common to virtually all yeast mRNAs. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in yeast by ribosome footprint profiling.The study includes 32 samples, comprised of 16 mRNA-Seq samples and 16 ribosome footprint profiling samples, derived from biological replicates of 3 mutant strains, ded1-cs, ded1-ts and tif1-ts, and the corresponding wild-type strains. The tif1-ts mutant and its wild-type counterpart were analyzed at 30°C and 37°C.

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Bone Marrow Mesenchymal Stromal Cells Support Translation in Refractory Acute Myeloid Leukemia

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