The Role of MSCs in the Development of Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a malignant disease of the bone marrow. The prognosis of AML is still poor with only 25% of patients living longer than 5 years. Thus, new therapeutic approaches are warranted to improve patients' survival. The growth of AML cells not only depends on cell intrinsic factors, but is also supported by stroma cells, among them mesenchymal stem cells (MSCs). We reported here that MSCs derived from human AML patients or murine models of human AML better supported the in vitro growth of leukemic cells than MSCs from non-leukemic patients or mice and this is dependent on cell-to-cell contact. Similarly, immortalized MSCs lines derived from AML patients supported the growth of human AML cell lines better than a MSC line originating from a healthy donor. In addition, the frequency of MSCsin the BM of leukemic mice was increased. On a molecular level, the polarization of MSCs towards an AML-supporting state depended on the expression of the transcription factor Growth factor independence 1 (Gfi1). Loss of Gfi1 abrogated the tumor-supporting state of AML-associated MSCs in vitro and in vivo. In summary, MSCs from AML patients support the growth of AML cells in vitro in a Gfi1-dependent manner which could open the path to new therapeutic approaches. DisclosuresDührsen:Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Khandanpour:Hospital of Essen university: Research Funding; Max-Eder: Research Funding.