Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype in AML cells through TGF-β-p38-ALDH2 pathway

Mesenchymal stromal cells (MSCs) in the bone marrow (BM) microenvironment have been shown to induce chemotherapy resistance in acute myeloid leukemia (AML) cells, but the mechanism is not clear. We hypothesized that stromal cells induce a stem-like phenotype in AML cells, thereby promoting tumorigenicity and chemotherapy resistance. We found that aldehyde dehydrogenase (ALDH), an enzyme that is highly expressed in hematopoietic as well as leukemic stem cells was dramatically activated in AML cells co-cultured with BM-MSCs mainly through upregulation of a specific isoform, ALDH2. Mechanistic studies revealed that stroma-derived TGF-{beta}1 induced an ALDH+ phenotype in AML cells via the non-canonical TGF-{beta} pathway through p38 activation. Inhibition of ALDH2 using specific inhibitors significantly inhibited BM-MSC-induced ALDH activity and sensitized AML cells to chemotherapy. Collectively, our data indicate that BM stroma induces a stem-like phenotype in AML cells through the non-canonical TGF-{beta} pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy. Impact StatementCurrently there is no standard therapy for AML. In this study we identified the mechanism of chemotherapy resistance in AML cells and discovered TGF-{beta}-p38-ALDH2 signaling pathway as a therapeutic target.