Targeting Microenvironmental Signals in Myeloid Malignancies

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). In support of a functional role of the niche in disease progression, our earlier work has shown that adhesive interaction of AML with endothelial cells is critical to maintain the therapy-resistant leukemia stem cells (LSCs). As an alternate to identifying niche-driven signals promoting leukemogenesis, we determined cell surface antigens expressed on LSCs that can act as receptors for these signals using our recent in vivo genome-wide CRISPR screen. To focus on signals likely to be cancer-specific, we selected a subset of novel cell-surface regulators with 2-fold higher expression in human bcCML LSCs compared to normal HSCs in our new RNA-seq dataset. Of these, the taurine transporter SLC6A6 (TauT) is of particular interest since its high expression is associated with poor prognosis in AML. Our experiments with the TauT genetic loss of function mouse indicate that TauT loss significantly impairs the propagation of aggressive myeloid leukemias in vivo by downregulating metabolic pathways including oxidative phosphorylation. Our work shows that while TauT inhibition significantly impairs the growth of patient derived myeloid leukemia cells, it does not impact the growth of normal human hematopoietic stem/progenitors. Finally, we identify the expanded osteolineage niche as a critical new source of taurine in the leukemic bone marrow microenvironment. Collectively, our studies identify TauT as an important new regulator of myeloid malignancies, and establish a novel role of taurine from the bone marrow osteoprogenitors in myeloid leukemia progression.

Calvi:Massachusetts General Hospital and Harvard Medical School: Patents & Royalties: U.S. Patent No. 8,802,104 B2; University of Rochester School of Medicine and Dentistry: Patents & Royalties: U.S. Patent No. 9,394,520.