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

## TL;DR

This study shows that HS6ST1 helps AML cancer cells resist chemotherapy by boosting TGF-β1 signaling, which could lead to new treatment strategies.

## Contribution

The novel finding is that HS6ST1 promotes chemotherapy resistance in AML through TGF-β1 signaling, offering a new therapeutic target.

## Key findings

- High HS6ST1 expression in AML patients with KMT2A-rearrangements correlates with worse survival and higher relapse risk.
- HS6ST1 depletion increases AML cell sensitivity to cytarabine and reduces TGF-β1 signaling.
- Blocking heparan sulfate with surfen enhances cytarabine's effectiveness in killing AML cells.

## Abstract

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 HS2ST1 and HS6ST1. Using AML patient cohort analyses, we demonstrate that increased HS6ST1 expression is associated with worse survival and increased relapse risk for AML patients harboring KMT2A-rearrangements. Using cell line derived xenografts, we show that AML cells depleted of HS2ST1, but not HS6ST1, have increased bone marrow leukemic burden. Further, AML cells depleted of HS6ST1 are more sensitive to cytarabine than Control cells, suggesting that HS6ST1 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 HS6ST1 depletion in AML cells reduces TGF-β1-mediated signaling, which diminishes cell survival upon cytarabine treatment. Together, our data show that HS6ST1 promotes AML cell chemotherapy resistance by supporting TGF-β1 signaling.