Xiao Lin, Karsa Mawar, Ronca Emma, Bongers Angelika, Kosciolek Angelika, El-Ayoubi Ali, Revalde Jezrael L, Seneviratne Janith A, Cheung Belamy B, Cheung Laurence C, Kotecha Rishi S, Newbold Andrea, Bjelosevic Stefan, Arndt Greg M, Lock Richard B, Johnstone Ricky W, Gudkov Andrei V, Gurova Katerina V, Haber Michelle, Norris Murray D, Henderson Michelle J, Somers Klaartje
Children's Cancer Institute, Lowy Cancer Research Institute, University of New South Wales, Randwick, NSW, Australia.
School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia.
Front Oncol. 2022 May 23;12:863329. doi: 10.3389/fonc.2022.863329. eCollection 2022.
Rearrangements of the () gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 () driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.
KMT2A基因重排在约10%的急性白血病中存在，并且是预后不良疾病的典型特征。由于开发针对KMT2A重排白血病的更好疗法的需求尚未满足，我们之前发现新型抗癌药物curaxin CBL0137可诱导癌细胞染色质解聚，延缓白血病进展，并增强临床前KMT2A重排白血病模型中标准护理化疗的效果。基于组蛋白去乙酰化酶（HDAC）抑制剂作为KMT2A重排白血病靶向抗癌药物的潜在前景，以及HDAC抑制剂也可使染色质解聚这一替代机制，我们研究了CBL0137是否能增强HDAC抑制剂帕比司他在KMT2A重排白血病模型中的疗效。CBL0137与帕比司他联合用药可通过凋亡迅速杀死KMT2A重排白血病细胞，并在MLL-AF9驱动的小鼠急性髓系白血病侵袭性模型中显著延缓白血病进展并延长生存期。该药物组合在源自KMT2A重排急性淋巴细胞白血病婴儿的快速进展异种移植模型中也产生了强烈的抗白血病反应，与单一疗法相比显著延长了生存期。CBL0137与帕比司他在KMT2A-r白血病细胞中的治疗增强作用似乎不是通过药物对重排相关组蛋白修饰的协同作用介导的。我们的数据已确定CBL0137/帕比司他组合是一种潜在的新型靶向治疗方法，可改善KMT2A重排白血病的预后。
