Hypoxia regulates CD9 expression and dissemination of B lymphoblasts
Hypoxia regulates CD9 expression and dissemination of B lymphoblasts
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DOI：
10.1016/j.leukres.2022.106964
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发表时间：
2022-11-03
影响因子：
2.7
通讯作者：
Gandemer, Virginie
中科院分区：
文献类型：
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作者：
Rouger-Gaudichon, Jeremie;Cousin, Elie;Gandemer, Virginie
急性淋巴细胞白血病（ALL）是儿童中最常见的癌症，最常源于b细胞前体。目前诊断后10年的存活率约为90%。然而，仍有15-20%的儿童复发，死亡风险很大。我们之前的工作表明，跨膜蛋白CD9在淋巴细胞迁移到避难所，特别是在睾丸中，通过C-X-C趋化因子配体12 （CXCL12）刺激淋巴细胞激活RAC1信号传导，在淋巴细胞迁移到避难所的过程中发挥重要作用。在这里，我们确定了骨髓和髓外壁龛共享的可上调CD9表达和功能的共同因子。我们发现低氧水平增强了CD9在mRNA和蛋白水平上的表达。我们进一步确定了参与缺氧反应的主转录因子HIF1 α直接结合CD9启动子并诱导CD9转录。我们还发现CD9蛋白在低氧水平下对白血病细胞粘附和迁移至关重要，可能是通过其对RAC1信号的作用。小鼠异种移植实验表明，HIF1 α信号通路以cd9依赖的方式促进ALL细胞的移植。目前的工作增加了我们对CD9在ALL发病机制中的意义的理解。
Acute lymphoblastic leukemias (ALL) are the most frequent cancer in children and derive most often from B-cell precursors. Current survival rates roughly reach 90% at 10 years from diagnosis. However, 15-20% of children still relapse with a significant risk of death. Our previous work showed that the transmembrane protein CD9 plays a major role in lymphoblasts migration into sanctuary sites, especially in testis, through the activation of RAC1 signaling upon blasts stimulation with C-X-C chemokine ligand 12 (CXCL12). Here, we identified common factors shared by the bone marrow and extramedullary niches which could upregulate CD9 expression and function. We found that low oxygen levels enhance CD9 expression both at mRNA and protein levels. We further determined that Hypoxia Inducible Factor 1 alpha (HIF1 alpha), the master transcription factor involved in hypoxia response, binds directly CD9 promoter and induce CD9 transcription. We also showed that CD9 protein is crucial for leukemic cell adhesion and migration at low oxygen levels, possibly through its action on RAC1 signaling. Mouse xenograft experiments indicate that HIF1 alpha signaling pathway promotes ALL cells engraftment in a CD9-dependent manner. The present work increments our understanding of CD9 implication in ALL pathogenesis.