Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells,STEM CELLS

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Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells
STEM CELLS ( IF 4.0 ) Pub Date : 2021-05-20 , DOI: 10.1002/stem.3387
Paul Jäger ₁ , Stefanie Geyh ₁ , Sören Twarock ₂ , Ron-Patrick Cadeddu ₁ , Pablo Rabes ₂ , Annemarie Koch ₁ , Uwe Maus ₃ , Tobias Hesper ₃ , Christoph Zilkens ₃ , Christina Rautenberg ₁ , Felix Bormann ₄ , Karl Köhrer ₅ , Patrick Petzsch ₅ , Dagmar Wieczorek ₆ , Beate Betz ₆ , Harald Surowy ₆ , Barbara Hildebrandt ₆ , Ulrich Germing ₁ , Guido Kobbe ₁ , Rainer Haas ₁ , Thomas Schroeder ₁

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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.

中文翻译：

急性髓性白血病诱导的健康 CD34+ 造血干细胞和祖细胞的功能抑制

急性髓性白血病 (AML) 的特征是白血病细胞的扩增和骨髓 (BM) 中正常造血前体的同时减少，导致造血功能不全，但人类对潜在机制知之甚少。假设白血病细胞通过体液因子在功能上抑制健康的 CD34+ 造血干细胞和祖细胞 (HSPC)，我们将健康的 BM 来源的 CD34+ HSPC 暴露于来自 AML 细胞系和 24 名新诊断的 AML 患者的无细胞上清液中。暴露于 AML 衍生的上清液显着抑制了健康 CD34+ HSPC 的增殖、细胞周期、集落形成和分化。暴露于白血病条件后健康 CD34+ HSPC 的 RNA 测序揭示了与增殖相关的基因的特定特征，细胞周期调节和分化，从而在分子水平上反映它们的功能抑制。配对患者样本的实验表明，这些抑制作用与免疫磁性富集的 CD34+ 白血病细胞群显着相关。使用 PCR、ELISA 和 RNA 测序，我们检测到 TGFβ1 在白血病细胞中的转录和蛋白质水平过表达，相应地，在健康 CD34+ HSPC 中检测到与 TGFβ1 信号传导相关的分子特征。TGFβ1 对健康造血的这种抑制作用在功能上得到证实，并且可以通过 SD208（一种 TGFβ 受体 1 信号传导抑制剂）在药理学上逆转。总体而言，这些数据表明，白血病细胞至少部分通过 TGFβ1 诱导健康 CD34+ HSPC 的功能性抑制，

更新日期：2021-05-20

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