BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells
BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells
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DOI：
10.1038/s41419-019-2203-z
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发表时间：
2020-01-06
影响因子：
9
通讯作者：
Erlacher, Miriam
中科院分区：
文献类型：
--
作者：
Afreen, Sehar;Bohler, Sheila;Erlacher, Miriam
抗凋亡BCL-2蛋白（BCL-2、BCL-XL、MCL-1、A1、BCL-W）抵消在发育期间和应激条件下出现的凋亡信号，并且因此对于每个细胞的存活是必需的。虽然在小鼠模型中充分描述了不同细胞类型的“BCL-2成瘾”，但关于不同抗凋亡BCL-2蛋白在给定人类细胞类型中的作用的信息有限。在这里，我们描述了BCL-XL对人类造血细胞的存活和功能的作用，目的是预测新型BCL-XL抑制BH 3模拟物的血液学副作用，并鉴定可能对此类抑制剂有反应的血液学恶性肿瘤。早期的临床研究表明，BCL-2/BCL-XL/BCL-W组合抑制剂Navitoclax（ABT-263）诱导由直接血小板死亡引起的重度血小板减少症，并被增加的巨核细胞生成抵消。相反，鼠研究已经报道了BCL-XL对晚期红系细胞和巨核细胞存活的重要贡献。使用慢病毒敲除，我们表明BCL-XL对人类造血细胞的作用比从小鼠数据和临床试验中预期的要明显得多。有效的遗传或化学BCL-XL抑制导致从红细胞生成的非常早期阶段开始的人红系细胞的显著损失，以及巨核细胞的减少。最重要的是，BCL-XL缺陷的人造血干细胞和多能祖细胞的数量减少，并且它们在异种移植期间在小鼠中移植的能力严重受损。BCL-2过表达完全补偿了BCL-XL缺陷，然而，其拮抗剂BIM的丧失并不导致人类红系细胞或干细胞和祖细胞的任何拯救。因此，我们得出结论，新的和具体的BCL-XL抑制剂可能是有效的治疗恶性肿瘤的红细胞或巨核细胞起源，如真性红细胞增多症，急性红细胞白血病，原发性血小板增多症或急性巨核细胞白血病。与此同时，可以预期它们将具有比Navitoclax更严重的血液学副作用。
The anti-apoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1, A1, BCL-W) counteract apoptotic signals emerging during development and under stress conditions, and are thus essential for the survival of every cell. While the "BCL-2 addiction" of different cell types is well described in mouse models, there is only limited information available on the role of different anti-apoptotic BCL-2 proteins in a given human cell type. Here we characterize the role of BCL-XL for survival and function of human hematopoietic cells, with the aim to predict hematological side effects of novel BCL-XL-inhibiting BH3-mimetics and to identify hematological malignancies potentially responsive to such inhibitors. Earlier clinical studies have shown that the combined BCL-2/BCL-XL/BCL-W inhibitor, Navitoclax (ABT-263) induces severe thrombocytopenia caused by direct platelet demise and counteracted by increased megakaryopoiesis. In contrast, murine studies have reported important contribution of BCL-XL to survival of late erythroid cells and megakaryocytes. Using lentiviral knockdown, we show that the roles of BCL-XL for human hematopoietic cells are much more pronounced than expected from murine data and clinical trials. Efficient genetic or chemical BCL-XL inhibition resulted in significant loss of human erythroid cells beginning from very early stages of erythropoiesis, and in a reduction of megakaryocytes. Most importantly, BCL-XL deficient human hematopoietic stem cells and multipotent progenitors were reduced in numbers, and they showed a severely impaired capacity to engraft in mice during xenotransplantation. BCL-XL deficiency was fully compensated by BCL-2 overexpression, however, loss of its antagonist BIM did not result in any rescue of human erythroid or stem and progenitor cells. We thus conclude that novel and specific BCL-XL inhibitors might be efficient to treat malignancies of erythroid or megakaryocytic origin, such as polycythemia vera, acute erythroid leukemia, essential thrombocytosis or acute megakaryocytic leukemia. At the same time, it can be expected that they will have more severe hematological side effects than Navitoclax.