Acute myeloid leukemia ‐induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells

Acute myeloid leukemia (AML)-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells (HSPC) via secreted factors. In particular transforming growth factor β1 (TGFβ1) plays a role in inhibition of key functions of healthy CD34+ HSPC and blockage of this pathway may serve as therapeutic target to improve hematopoiesis in patients with AML. AbstractAcute myeloid leukemia (AML) is characterized by an expansion of leukemic cells and a simultaneous reduction of normal hematopoietic precursors in the bone marrow (BM) resulting in hematopoietic insufficiency, but the underlying mechanisms are poorly understood in humans. Assuming that leukemic cells functionally inhibit healthy CD34+ hematopoietic stem and progenitor cells (HSPC) via humoral factors, we exposed healthy BM-derived CD34+ HSPC to cell-free supernatants derived from AML cell lines as well as from 24 newly diagnosed AML patients. Exposure to AML-derived supernatants significantly inhibited proliferation, cell cycling, colony formation, and differentiation of healthy CD34+ HSPC. RNA sequencing of healthy CD34+ HSPC after exposure to leukemic conditions revealed a specific signature of genes related to proliferation, cell-cycle regulation, and differentiation, thereby reflecting their functional inhibition on a molecular level. Experiments with paired patient samples showed that these inhibitory effects are markedly related to the immunomagnetically enriched CD34+ leukemic cell population. U...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Translational and Clinical Research Source Type: research