Aubrey Brandon J, Cutler Jevon A, Bourgeois Wallace, Donovan Katherine A, Gu Shengqing, Hatton Charlie, Perlee Sarah, Perner Florian, Rahnamoun Homa, Theall Alexandra C P, Henrich Jill A, Zhu Qian, Nowak Radosław P, Kim Young Joon, Parvin Salma, Cremer Anjali, Olsen Sarah Naomi, Eleuteri Nicholas A, Pikman Yana, McGeehan Gerard M, Stegmaier Kimberly, Letai Anthony, Fischer Eric S, Liu X Shirley, Armstrong Scott A
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Nat Cancer. 2022 May;3(5):595-613. doi: 10.1038/s43018-022-00366-1. Epub 2022 May 9.
Acute myeloid leukemia (AML) remains difficult to treat and requires new therapeutic approaches. Potent inhibitors of the chromatin-associated protein MENIN have recently entered human clinical trials, opening new therapeutic opportunities for some genetic subtypes of this disease. Using genome-scale functional genetic screens, we identified IKAROS (encoded by IKZF1) as an essential transcription factor in KMT2A (MLL1)-rearranged (MLL-r) AML that maintains leukemogenic gene expression while also repressing pathways for tumor suppression, immune regulation and cellular differentiation. Furthermore, IKAROS displays an unexpected functional cooperativity and extensive chromatin co-occupancy with mixed lineage leukemia (MLL)1-MENIN and the regulator MEIS1 and an extensive hematopoietic transcriptional complex involving homeobox (HOX)A10, MEIS1 and IKAROS. This dependency could be therapeutically exploited by inducing IKAROS protein degradation with immunomodulatory imide drugs (IMiDs). Finally, we demonstrate that combined IKAROS degradation and MENIN inhibition effectively disrupts leukemogenic transcriptional networks, resulting in synergistic killing of leukemia cells and providing a paradigm for improved drug targeting of transcription and an opportunity for rapid clinical translation.
急性髓系白血病（AML）的治疗仍然困难，需要新的治疗方法。染色质相关蛋白MENIN的强效抑制剂最近已进入人体临床试验，为该疾病的一些基因亚型开辟了新的治疗机会。通过全基因组功能基因筛选，我们确定IKAROS（由IKZF1编码）是KMT2A（MLL1）重排（MLL-r）AML中的一种必需转录因子，它维持白血病发生相关基因的表达，同时也抑制肿瘤抑制、免疫调节和细胞分化途径。此外，IKAROS与混合谱系白血病（MLL）1-MENIN和调节因子MEIS1表现出意想不到的功能协同作用和广泛的染色质共占据，以及涉及同源盒（HOX）A10、MEIS1和IKAROS的广泛造血转录复合物。这种依赖性可以通过使用免疫调节性酰亚胺药物（IMiDs）诱导IKAROS蛋白降解来进行治疗性利用。最后，我们证明联合IKAROS降解和MENIN抑制可有效破坏白血病发生转录网络，导致白血病细胞的协同杀伤，并为改善转录药物靶向提供范例以及快速临床转化的机会。
