Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.
Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.
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DOI：
10.1186/s40164-023-00445-8
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发表时间：
2023-09-22
影响因子：
10.9
通讯作者：
Stam, Ronald W.
中科院分区：
文献类型：
--
作者：
Schneider, Pauline;Crump, Nicholas T.;Arentsen-Peters, Susan T. C. J. M.;Smith, Alastair L.;Hagelaar, Rico;Adriaanse, Fabienne R. S.;Bos, Romy S.;de Jong, Anja;Nierkens, Stefan;Koopmans, Bianca;Milne, Thomas A.;Pieters, Rob;Stam, Ronald W.
在KMT2A-重排的急性淋巴细胞白血病(ALL)中，一种侵袭性的恶性肿瘤，致癌的KMT2A-融合蛋白不适当地招募DOT1L来促进白血病的发生，突出了DOT1L作为一个有吸引力的治疗靶点。不幸的是，用一流的DOT1L抑制剂Pinometostat治疗最终会导致无反应。为了了解这一点，我们在儿科KMT2A：：AFF1+B-ALL细胞中建立了获得性血压调节器抵抗。有趣的是，这些细胞在很大程度上独立于DOT1L介导的H3K79甲基化，但仍然依赖于DOT1L、HOXA9和KMT2A：：AFF1融合的物理存在。此外，这些细胞选择性地失去了多种KMT2A融合靶基因的表观遗传调控和表达，如PROM1/CD133，而其他KMT2A：：AFF1靶基因，包括HOXA9和CDK6，没有受到影响。与此同时，这些抗血压药物的细胞显示出几个髓系相关基因的上调，包括CD33和LILRB4/CD85k。综上所述，该模型全面展示了KMT2A-重新排列所有细胞在失去对其主要致癌属性之一的依赖时的适应潜力。网上版载有补充材料，可在10.1186/s40164023-00445-8查阅。
In KMT2A-rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2A::AFF1+ B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2A::AFF1 fusion. Moreover, these cells selectively lost the epigenetic regulation and expression of various KMT2A-fusion target genes such as PROM1/CD133, while other KMT2A::AFF1 target genes, including HOXA9 and CDK6 remained unaffected. Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A-rearranged ALL cells upon losing dependency on one of its main oncogenic properties. The online version contains supplementary material available at 10.1186/s40164-023-00445-8.
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影响因子：
30.8
作者：
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St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
影响因子：
11.4
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影响因子：
3.2
作者：
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通讯作者：
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影响因子：
4.6
作者：
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通讯作者：
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影响因子：
3.4
作者：
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