Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia
Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia
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DOI：
10.1186/s13045-019-0749-y
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发表时间：
2019-06-28
影响因子：
28.5
通讯作者：
Stresemann, Carlo
中科院分区：
文献类型：
--
作者：
Brzezinka, Krzysztof;Nevedomskaya, Ekaterina;Stresemann, Carlo
混合谱系白血病基因MLL（KMT 2A）的染色体重排已被广泛表征为白血病中的一个强有力的致癌驱动因子。对于其致癌功能，大多数MLL融合蛋白利用多酶超延伸复合物导致MLL靶基因的表达升高。MLL靶基因的高表达覆盖了正常的造血分化程序，导致以自我更新能力为特征的未分化胚细胞。尽管大量的资源致力于提高对治疗靶点的理解，以克服ALL/AML中的去分化，但靶点的相互依赖性仍然没有得到很好的描述。大多数的抑制剂可能干扰MLL融合蛋白驱动的转化已在个别研究，这到目前为止阻碍了他们的直接crosscomparing.MethodsIn我们的研究，我们的特点是头对头的临床阶段抑制剂BET，DHODH，DOT 1 L以及两个新的抑制剂CDK 9和Menin-MLL相互作用的分化诱导的重点。我们在一个大的细胞系面板中分析了这些抑制剂对全局基因表达的影响，并检查了细胞反应，如增殖抑制、凋亡诱导、细胞周期阻滞、表面标志物表达、形态表型变化和吞噬作用作为功能分化读数。我们还验证了这些抑制剂的组合潜力的增殖和分化level.ResultsOur的分析显示分化诱导和调制MLL融合靶基因表达的显着差异。我们观察到Menin-MLL和DOT 1 L抑制剂非常特异性地作用于MLL融合的白血病细胞系，而BET、DHODH和P-TEFb的抑制剂具有超出MLL融合的强烈作用。在AML/ALL癌症模型中，检测到Menin-MLL、DOT 1 L和DHODH抑制剂的显著分化作用，而BET和CDK 9抑制剂主要诱导细胞凋亡。对于第一次，我们探讨了上述抑制剂的组合潜力方面克服分化block.ConclusionOur的研究结果显示这些抑制剂的分子活性的实质性的多样性，并提供了有价值的见解，进一步发展潜力作为单一药物或组合在MLL融合白血病。
IntroductionThe chromosomal rearrangements of the mixed-lineage leukemia gene MLL (KMT2A) have been extensively characterized as a potent oncogenic driver in leukemia. For its oncogenic function, most MLL-fusion proteins exploit the multienzyme super elongation complex leading to elevated expression of MLL target genes. High expression of MLL target genes overwrites the normal hematopoietic differentiation program, resulting in undifferentiated blasts characterized by the capacity to self-renew. Although extensive resources devoted to increased understanding of therapeutic targets to overcome de-differentiation in ALL/AML, the inter-dependencies of targets are still not well described. The majority of inhibitors potentially interfering with MLL-fusion protein driven transformation have been characterized in individual studies, which so far hindered their direct cross-comparison.MethodsIn our study, we characterized head-to-head clinical stage inhibitors for BET, DHODH, DOT1L as well as two novel inhibitors for CDK9 and the Menin-MLL interaction with a focus on differentiation induction. We profiled those inhibitors for global gene expression effects in a large cell line panel and examined cellular responses such as inhibition of proliferation, apoptosis induction, cell cycle arrest, surface marker expression, morphological phenotype changes, and phagocytosis as functional differentiation readout. We also verified the combination potential of those inhibitors on proliferation and differentiation level.ResultsOur analysis revealed significant differences in differentiation induction and in modulating MLL-fusion target gene expression. We observed Menin-MLL and DOT1L inhibitors act very specifically on MLL-fused leukemia cell lines, whereas inhibitors of BET, DHODH and P-TEFb have strong effects beyond MLL-fusions. Significant differentiation effects were detected for Menin-MLL, DOT1L, and DHODH inhibitors, whereas BET and CDK9 inhibitors primarily induced apoptosis in AML/ALL cancer models. For the first time, we explored combination potential of the abovementioned inhibitors with regards to overcoming the differentiation blockage.ConclusionOur findings show substantial diversity in the molecular activities of those inhibitors and provide valuable insights into the further developmental potential as single agents or in combinations in MLL-fused leukemia.