Requirement for CDK6 in MLL-rearranged acute myeloid leukemia
Requirement for CDK6 in MLL-rearranged acute myeloid leukemia
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DOI：
10.1182/blood-2014-02-558114
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发表时间：
2014-07-03
期刊：
影响因子：
20.3
通讯作者：
Froehling, Stefan
中科院分区：
文献类型：
--
作者：
Placke, Theresa;Faber, Katrin;Froehling, Stefan
涉及H3 K4甲基转移酶的混合系白血病（MLL）的染色体重排触发造血祖细胞中的异常基因表达并引起急性髓细胞白血病（AML）的侵袭性亚型。对MLL融合介导的白血病发生的见解尚未转化为更好的治疗方法，因为MLL难以直接靶向，并且MLL下游基因的身份（其改变的转录介导白血病转化）注释不足。我们使用功能遗传学方法来揭示由MLL-AF 9驱动的AML细胞异常依赖于细胞周期调节因子CDK 6，而不是其功能同系物CDK 4，并且CDK 6耗尽诱导的优先生长抑制是通过增强骨髓分化介导的。CDK 6的重要性在携带交替MLL融合的AML细胞和MLL-AF 9驱动的白血病的小鼠模型中也是明显的，并且可以归因于突变MLL对CDK 6的转录激活。重要的是，降低CDK 6表达的背景依赖性作用被目前临床开发中的小分子CDK 6抑制剂密切表型模仿。这些数据确定CDK 6作为白血病发生中MLL融合的关键效应子，其可能被靶向以克服与MLL重排AML相关的分化阻滞，并强调细胞周期调节因子在不同背景下可能具有独特的、非经典的和非冗余的功能。
Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts.