Microenvironment Meshes With Metabolism: Dissecting the Taurine–Taurine Transporter Axis in Acute Myeloid Leukemia Free

“When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.” So wrote the English surgeon Steven Paget in 1889, formulating the concept that the tumor microenvironment (TME) is an active participant in cancer evolution.¹  Over the following decades, foundational studies on the hematopoietic stem cell niche and its perturbation in myeloid malignancy, combined with advances in animal disease models, organoids, and single-cell and spatial transcriptomics, have reinvigorated and affirmed the key enabling role of the TME in leukemia.²  Yet the specific cell–cell interactions mediated by ligand-receptor dynamics in the bone marrow that shape the disease trajectory are incompletely described — and, in many cases, have not been functionally validated. Sonali Sharma, PhD, and colleagues have identified that mesenchymal and osteolineage stromal cells locally supply the ligand taurine, a small molecule metabolite, which upon binding its cognate receptor on leukemic stem cells drives cell survival and disease progression.³ 

Dr. Sharma and her fellow researchers began by building a ligand-receptor interactome in the leukemia TME. Single-cell RNA sequencing (RNA-seq) data from stromal cells in a nonirradiated murine leukemia model across disease stages generated a list of potential ligands and demonstrated dynamic niche remodeling over the course of leukemogenesis. Next, the authors created a shortlist of functionally required candidate receptors by intersecting differentially expressed cell surface receptor genes in bulk RNA-seq from leukemia samples with dependencies identified in a genome-wide in vivo leukemia CRISPR dropout screen.⁴  They honed their analysis to focus on ligands that are selectively upregulated during disease progression (indicating relevance to leukemia maintenance) and associate with an adverse leukemia prognosis in external datasets.

The taurine–taurine transporter (TAUT) ligand-receptor pair stood out. The TAUT receptor (encoded by SLC6A6) facilitates the transport of both taurine and beta-alanine, but only the enzymes required for taurine biosynthesis (CDO1 and CSAD) are expressed specifically in mesenchymal and osteolineage stromal cells, pointing to a niche-derived, taurine-specific signaling loop. CDO1 expression, taurine levels, and SLC6A6 are all upregulated in human leukemic samples compared to controls.

The authors went on to genetically or pharmacologically manipulate each component of this axis to highlight that the supply of taurine serves as a cell-extrinsic driver of leukemogenesis. Inhibiting stromal production of taurine in coculture assays led to a reduction in both the viability and colony-formation potential of leukemic cells, which could be rescued by taurine supplementation. Conditional deletion of CDO1 in mesenchymal and osteolineage stromal cells to selectively prevent taurine biosynthesis led to a survival advantage in a murine leukemia model, as did inhibition of taurine uptake by deletion of the cognate receptor SLC6A6 on leukemic stem cells (LSCs). TAUT upregulation co-occurs with venetoclax resistance in external datasets, and taurine withdrawal dampened BCL2 expression. Taurine inhibition — leveraging well-characterized structural analogues — led to a selective reduction of acute myeloid leukemia (AML) colony-forming assays but did not impact healthy human CD34+ hematopoietic stem and progenitor cells. It also synergized with venetoclax to reduce colony formation in primary patient AML cells and extend xenograft survival beyond each individual agent, providing data to support the fact that this finding may be clinically actionable.

Mechanistic studies focused on the Rag GTPase–mTORC1 axis: genetic knockdown of the SLC6A6 transporter drove a reduction in mTORC1 activity, glycolytic gene expression, and glucose flux. This positions taurine as a cell-extrinsic trigger for glycolysis to promote macromolecule generation supporting rapid LSC growth and proliferation.

The concept of a niche-derived metabolite sustaining leukemia is not entirely novel. Pediatric hematologists will recognize the precedent of asparaginase, which has been in use since the 1960s to deplete asparagine, a key oncometabolic dependency in acute lymphoblastic leukemia.⁵  The universality of the taurine–TAUT axis across leukemia subtypes, and its tractability as a therapeutic target, remain to be established. This study extends our current understanding of the metabolic crosstalk between the “soil” of the niche and the “seed” of leukemic cells — and raises a cautionary flag. Taurine is abundant in the human diet — present in seafood, dark meat, seaweed, and dairy — and is widely used in supplements and energy drinks, including for the management of chemotherapy-induced nausea.⁶  Whether restricting dietary intake or blocking uptake could inhibit clonal expansion is an open and actionable question in the treatment of leukemia.