AML-241: Bone Marrow Stromal Cells Induce Chemotherapy Resistance in AML Cells through TGF-β-p38-ALDH2 Pathway

Abstract

Context Chemotherapy resistance is one of the leading causes of disease progression and relapse in patients with acute myeloid leukemia (AML). The interaction between mesenchymal stromal cells (MSCs) and AML cells in the bone marrow (BM) is critical for leukemogenesis and chemotherapy resistance. Objective As tumor initiation and chemotherapy resistance are characteristic features of leukemia stem cells, we hypothesize that BM-MSCs induce a stem-like phenotype in AML cells. The objectives of this study are to determine the effect of stromal cells on the stem cell function of AML cells and to identify signaling pathways that support AML-stroma interactions in the BM microenvironment. Design We cultured AML cell lines and patient samples with or without BM-MSCs and measured aldehyde dehydrogenase (ALDH) activity in AML cells by ALDEFLUOR™ assay. In addition, we performed genomic and proteomic analyses to identify signaling pathways that support AML-stroma interactions. Finally, we used specific inhibitors that target ALDH activity to sensitize AML cells to chemotherapeutic agents. Results Co-culture of AML cells with BM-MSCs significantly induced ALDH activity in AML cells, mainly through upregulation of ALDH2 and ALDH1L2 isoforms. TCGA data analysis revealed that ALDH2 is a prognostic factor in AML. Mechanistic studies revealed that TGF-β1-regulated gene signature is activated in AML cells co-cultured with stromal cells. Knockdown of TGF-β1 in BM-MSCs inhibited stroma-induced ALDH activity and ALDH2 expression in AML cells, whereas treatment with recombinant TGF-β1 induced an ALDH+ phenotype in AML cells. We also found that the non-canonical TGF-β pathway, through p38 activation, regulates ALDH2 expression in AML cells. Pharmacologic inhibition of ALDH2 significantly inhibited BM-MSC-induced ALDH activity and sensitized AML cells to chemotherapy. Conclusion BM-MSCs induce ALDH+ stem cell phenotype in AML cells through the non-canonical TGF-β pathway. ALDH2 is the crucial isoform regulating ALDH activity in AML cells and is a prognostic factor. Pharmacologic inhibition of ALDH2 sensitizes AML cells to standard chemotherapy. Grant Acknowledgement This study is partially supported by Leukemia SPORE CDA, IRG from MDACC, Cure Sonia Foundation and Golfer's Against Cancer to VLB. NIH (CA055164), MDACC Support Grant (CA016672), CPRIT-MIRA, and Paul and Mary Haas Chair in Genetics to MA.