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00:00Signals from the microenvironment are known to be critical for development,

00:04stem cell self-renewal and oncogenic progression.

00:07Although some niche-driven signals that promote cancer progression have been identified 1, 2,

00:123, 4, 5, concerted efforts to map disease-relevant microenvironmental ligands of

00:17cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA sequencing,

00:24scRNA-seq, to identify molecular cues from the bone marrow stromal niche that engage

00:29leukemia stem-enriched cells, LSCs, during oncogenic progression.

00:34We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC

00:40dependencies 6 to identify LSC niche interactions that are essential for leukomogenesis.

00:45These analyses identify the taurine-taurine transporter, taught, axis as a critical

00:51dependency of aggressive myeloid leukemias. We find that cysteine-dioxygenase type 1, CDO1,

00:58driven taurine biosynthesis is restricted to osteolineage cells and increases during myeloid

01:05disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and

01:11improves survival outcomes. Using taught genetic loss-of-function mouse models and patient-derived

01:17acute myeloid leukemia, AML, cells, we show that taught inhibition significantly impairs in vivo

01:23myeloid leukemia progression. Consistent with elevated taught expression in venetoclax-resistant

01:29AML, taught inhibition synergizes with venetoclax to block the growth of primary human AML cells.

01:37Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAGGTP-dependent

01:43MTOR activation and downstream glycolysis. Collectively, our work establishes the temporal

01:49landscape of stromal signals during leukemia progression and identifies taurine as a key

01:54regulator of myeloid malignancies.