In acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify the role of environmental syntenin in the progression of AML. By in vivo approaches in syngeneic mice, we demonstrate that a syntenin-deficient environment reprograms AML blasts to survive independently of the stroma. Up-regulation of EEF1A2 in the blasts controls this gain of cell survival. Furthermore, using ex vivo co-culture systems, we show that syntenin-deficient bone marrow stromal cells (BMSC) enhance the survival of different types of AML cells, including patient samples, and suffice to educate syngeneic AML, recapitulating micro-environmental effects observed in vivo. We establish that syntenin-deficiency causes an increase of eIF5A and autophagy-related factors in BMSC, and provide evidence that the inhibition of autophagy prevents syntenin-deficient BMSC to stimulate AML survival. Altogether, these findings indicate that host-syntenin in the BM microenvironment acts as a repressor of AML aggressiveness.

中文翻译：

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Syntenin缺陷的微环境教育AML的侵略性

在急性髓细胞性白血病（AML）中，基质微环境在促进肿瘤细胞存活和进展中起着重要作用。尽管已被广泛研究，但白血病和基质细胞之间的串扰仍然知之甚少。Syntenin是一种多域PDZ蛋白，可控制参与细胞间通讯的关键分子的运输和信号传导。因此，我们旨在阐明环境合成素在AML进展中的作用。通过体内同源基因小鼠的方法，我们证明了协同蛋白缺乏的环境会重新编程AML blasts，使其独立于基质而存活。原始细胞中EEF1A2的上调控制了细胞存活的这种增加。此外，使用离体共培养系统，我们显示，Syntenin缺陷型骨髓基质细胞（BMSC）增强了不同类型AML细胞（包括患者样品）的存活率，足以教育同基因AML，概括了体内观察到的微环境效应。我们建立，Syntenin缺陷导致BMSC中eIF5A和自噬相关因子的增加，并提供证据表明自噬的抑制阻止了Syntenin缺陷BMSC刺激AML生存。总而言之，这些发现表明BM微环境中的宿主syntenin充当AML侵袭性的阻遏物。并提供证据表明自噬的抑制作用阻止了联蛋白缺乏的BMSC刺激AML存活。总而言之，这些发现表明BM微环境中的宿主syntenin充当AML侵袭性的阻遏物。并提供证据表明自噬的抑制作用阻止了联蛋白缺乏的BMSC刺激AML存活。总而言之，这些发现表明BM微环境中的宿主syntenin充当AML侵袭性的阻遏物。