HS6ST1 regulates acute myeloid leukemia chemotherapy resistance via TGF-β1 signaling.

Despite therapeutic advances, relapse remains the leading cause of death in patients with acute myeloid leukemia (AML). Growth factor signaling controls AML survival, proliferation, relapse, and chemotherapy resistance. Here, we studied heparan sulfate proteoglycans, a class of molecules that bind growth factors via their heparan sulfate chains to change their signaling ability. Heparan sulfate-growth factor interactions are controlled by the addition of sulfate groups catalyzed by heparan sulfotransferases, such as those encoded by and . Using AML patient cohort analyses, we demonstrate that increased expression is associated with worse survival and increased relapse risk for AML patients harboring -rearrangements. Using cell line derived xenografts, we show that AML cells depleted of , but not , have increased bone marrow leukemic burden. Further, AML cells depleted of are more sensitive to cytarabine than Control cells, suggesting that regulates AML chemotherapy resistance. Heparan sulfate antagonism with surfen synergized with cytarabine to further support AML cell death compared to cytarabine alone. Mechanistically, we demonstrate that depletion in AML cells reduces TGF-β1-mediated signaling, which diminishes cell survival upon cytarabine treatment. Together, our data show that promotes AML cell chemotherapy resistance by supporting TGF-β1 signaling.