High HDAC8 Creates Targetable Vulnerabilities in Acute Myeloid Leukemia through Dysregulation of BRCA1-Related RNA Splicing Machinery and Defective DNA Damage Repair

• Published in: Blood 2024-11, Vol.144, p.1398-1398
• Main Authors: Zhang, Lianjun, Fu, Yu-Hsuan, Hua, Wei-Kai, Nguyen, Le Xuan Truong, He, Xin, Guo, Wancheng, Zhu, Yinghui, Chen, Ying-Chieh, Chen, Zhenhua, Dong, Haojie, Zhang, Lei, Zhang, Bin, Stark, Jeremy, Li, Ling, Marcucci, Guido, Kuo, Ya-Huei
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-208137

Inv(16) [inv(16)(p13q22) or t(16;16)(p13.1;q22)], a common recurrent chromosomal translocation in acute myeloid leukemia (AML), creates CBFb-MYH11 (CM) leukemogenic fusion gene by fusing core binding factor CBFb with smooth muscle myosin heavy chain gene MYH11. Despite the relatively favorable prognosis of inv(16) patients, only about 50-60% achieve long-term survival with standard chemotherapy, highlighting the need for novel therapies to achieve cure. We previously reported that CM fusion protein physically interacts with HDAC8 and enhances its activity, which is critical for CM-driven leukemogenesis. We also presented CM expression increases DNA damage and impairs homologous recombination-directed repair through novel HDAC8-mediated mechanisms. HDAC8 interacts with BRCA1, BCLAF1, and U2AF1 as part of the RNA splicing machinery, critical for efficient DNA damage repair. HDAC8 deacetylates U2AF1, thereby disrupting the recruitment of BRCA1/BCLAF1 to RNA splicing machinery. Accordingly, CM expression, through enhanced HDAC8 activity, leads to dysregulated RNA splicing and defective DNA repair. Our analysis of the TARGET dataset revealed higher HDAC8 expression in AML samples compared to healthy controls (HL) and high HDAC8 (top 25%) is significantly correlated with increased DDR signature score (GO:00006974) in both TARGET and Beat AML datasets. We postulated that HDAC8-high malignant cells, including CM-AML, may exhibit increased sensitivity to splicing modulators or PARP inhibitors (PARPi). First, we evaluated the effects of H3B-8800 (H3B; an orally bioavailable small molecule inhibitor for SF3B complex) and PARPi (Olaparib or Talazoparib) in primary murine CM-AML cells. Compared to normal bone marrow (BM) cells, CM-AML cells showed significantly increased sensitivity to H3B (IC50: 55.21 ± 9.585 vs. 432.0 ± 21.49 nM; p