Phosphoproteomics and Proteomics of wild-type and TauT-/- leukemia cells

ABSTRACT: Signals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified, concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR based in vivo LSC dependency map7 to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth in vitro and improves survival outcomes in vivo. Using TauT genetic loss of function murine models and patient-derived AML cells, we show that TauT inhibition significantly impairs in vivo myeloid leukemia progression. Consistent with elevated TauT expression in venetoclax resistant AML, TauT inhibition synergizes with venetoclax to block growth of primary human AML cells. Mechanistically, our metabolomic, proteomic and transcriptomic approaches indicate that loss of taurine uptake inhibits Rag-GTP dependent mTOR activation and downstream glycolytic metabolism. Collectively, our work establishes the temporal landscape of stromal signals during leukemia progression and identifies taurine as an important regulator of myeloid malignancies.

INSTRUMENT(S): Orbitrap Astral

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, Stem Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Kyle Swovick  

LAB HEAD: Jeevisha Bajaj

PROVIDER: PXD062322 | Pride | 2025-03-28

REPOSITORIES: Pride