Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia
Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia
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DOI：
10.1172/jci39964
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Tomasson, Michael H.
中科院分区：
文献类型：
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作者：
Xiang, Zhifu;Luo, Hui;Tomasson, Michael H.
抗凋亡的bcl2家族成员参与了急性髓系白血病(AML)的发病过程，但单个蛋白(如bcl2、bclxl和髓系细胞白血病1[MCL1])的功能意义和相对重要性仍不清楚。在这里，我们检测了BCL2、BCL-XL和MCL1在原代人类造血亚群和AML患者的白血病原始细胞中的表达，发现MCL1转录本在所有被测试的样本中都持续高水平表达。与此一致的是，在Myc诱导的AML小鼠模型中，MCL1蛋白也在髓系白血病细胞中高表达。我们使用这个模型来检验这样的假设，即MCL1通过允许髓系祖细胞逃避Myc诱导的细胞死亡来促进AML的发展。事实上，在活体中激活Myc 7天显著增加了髓系细胞的数量，而造血干细胞、祖细胞和B系细胞则被耗尽。此外，MCL1单倍体缺陷抑制了AML的发展。此外，从完全转化的AML细胞中删除MCL1的单一等位基因大大延长了移植小鼠的存活时间。相反，通过在MCL1单倍体不足的细胞中共表达Bcl2和Myc，可以恢复疾病的快速致死性。综上所述，这些数据显示了MCL1在小鼠AML发病机制中的关键作用和剂量依赖关系，并表明MCL1可能是初治AML患者的一个有前途的治疗靶点。
Antiapoptotic BCL2 family members have been implicated in the pathogenesis of acute myelogenous leukemia (AML), but the functional significance and relative importance of individual proteins (e.g., BCL2, BCL-XL, and myeloid cell leukemia 1 [MCL1]) remain poorly understood. Here, we examined the expression of BCL2, BCL-XL, and MCL1 in primary human hematopoietic subsets and leukemic blasts from AML patients and found that MCL1 transcripts were consistently expressed at high levels in all samples tested. Consistent with this, Mcl1 protein was also highly expressed in myeloid leukemic blasts in a mouse Myc-induced model of AML. We used this model to test the hypothesis that Mcl1 facilitates AML development by allowing myeloid progenitor cells to evade Myc-induced cell death. Indeed, activation of Myc for 7 days in vivo substantially increased myeloid lineage cell numbers, whereas hematopoietic stem, progenitor, and B-lineage cells were depleted. Furthermore, Mcl1 haploinsufficiency abrogated AML development. In addition, deletion of a single allele of Mcl1 from fully transformed AML cells substantially prolonged the survival of transplanted mice. Conversely, the rapid lethality of disease was restored by coexpression of Bcl2 and Myc in Mcl1-haploinsufficient cells. Together, these data demonstrate a critical and dose-dependent role for Mcl1 in AML pathogenesis in mice and suggest that MCL1 may be a promising therapeutic target in patients with de novo AML.