Abstract 6653: Taurine Transporter <i>SLC6A6</i> promotes myeloid leukemia progression by regulating glycolysis

Abstract Interactions of stem cells with their surrounding microenvironment are known to be essential for both normal development and for sustaining self-renewing adult stem cells, such as the hematopoietic stem cells (HSCs). Since cancers often hijack developmental signals for their progression, it is likely that niche-driven signals that sustain HSCs also influence the growth of leukemias arising from mutations in HSCs and early hematopoietic progenitors, such as acute myeloid leukemia (AML) and blast crisis chronic myeloid leukemia (bcCML). To identify candidate cell surface receptors essential for myeloid leukemia progression, we employed a comprehensive approach integrating our in vivo genome-wide CRISPR screen and our RNA-seq analysis of human LSCs from distinct myeloid leukemia subtypes. Of these, the taurine transporter (TauT), encoded by SLC6A6, was of particular interest since its expression is associated with poor prognosis in acute myeloid leukemia (AML) patients. Our experiments using TauT knockout mice indicate that TauT loss significantly impairs myeloid leukemia progression in vivo. An RNA-Seq analysis of freshly isolated TauT+/+ and TauT-/- leukemia cells identified a striking decrease in glycolysis associated genes in the absence of TauT. Consistent with this, Seahorse analysis showed significantly reduced basal glycolysis and glycolytic capacity in TauT-/- LSCs as compared to TauT+/+ controls. In addition, inhibiting TauT reduced the abundance of key glycolytic metabolites as measured by LC/MS spectrometry. Our experiments showing significant downregulation of mTOR pathway in the absence of TauT indicate that mTOR signaling may regulate glycolysis in leukemia cells. Consistent with a functional role of mTOR downstream of TauT function, our data shows that activating mTOR pathway in TauT-/- cells can rescue expression of glycolysis related genes and leukemic cell growth. Importantly, our experiments inhibiting TauT using shRNAs or small-molecule inhibitors identify a key role of this signal in the growth of patient-derived myeloid leukemia cells. Collectively, our data identify a critical requirement of the taurine-TauT axis in myeloid leukemia progression and indicate that the TauT inhibition may be of therapeutic value in myeloid leukemia. Citation Format: Sonali Sharma, Benjamin J. Rodems, Cameron D. Baker, Christina M. Kaszuba, Edgardo I. Franco, Takashi Ito, Laura M. Calvi, Michael W. Becker, Bradley R. Smith, Paul S. Brookes, Joshua C. Munger, Jane L. Liesveld, Craig T. Jordan, John M. Ashton, Jeevisha Bajaj. Taurine Transporter SLC6A6 promotes myeloid leukemia progression by regulating glycolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6653.