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Acute myeloid leukemia‐induced functional inhibition of healthy CD34 + hematopoietic stem and progenitor cells
Author(s) -
Jäger Paul,
Geyh Stefanie,
Twarock Sören,
Cadeddu RonPatrick,
Rabes Pablo,
Koch Annemarie,
Maus Uwe,
Hesper Tobias,
Zilkens Christoph,
Rautenberg Christina,
Bormann Felix,
Köhrer Karl,
Petzsch Patrick,
Wieczorek Dagmar,
Betz Beate,
Surowy Harald,
Hildebrandt Barbara,
Germing Ulrich,
Kobbe Guido,
Haas Rainer,
Schroeder Thomas
Publication year - 2021
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.3387
Subject(s) - haematopoiesis , cd34 , biology , progenitor cell , myeloid leukemia , myeloid , bone marrow , stem cell , cancer research , leukemia , immunology , hematopoietic stem cell , microbiology and biotechnology
Acute 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. Using PCR, ELISA, and RNA sequencing, we detected overexpression of TGFβ1 in leukemic cells on the transcriptional and protein level and, correspondingly, a molecular signature related to TGFβ1 signaling in healthy CD34+ HSPC. This inhibitory effect of TGFβ1 on healthy hematopoiesis was functionally corrobated and could be pharmacologically reverted by SD208, an inhibitor of TGFβ receptor 1 signaling. Overall, these data indicate that leukemic cells induce functional inhibition of healthy CD34+ HSPC, at least in part, through TGFβ1, suggesting that blockage of this pathway may improve hematopoiesis in AML.

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