Abstract A012: Targeting proteasome vulnerabilities for the treatment of monosomy 7 associated blood disorders

• DOI: 10.1158/1538-8514.synthleth24-a012
• Publication Date: 2024-06-10T07:06:18Z
• Authors: Haijiao Zhang; Basil Allen; Daniel Bottomly; Peter Ryabinin; Schannon K. Mcweeney
• Keywords: Haploinsufficiency; Gene dosage; Monosomy

Abstract Monosomy 7 is among the most frequent cytogenetic abnormalities in hematological disorders and associated with short survival drug resistance. Despite its high prevalence detrimental impact, therapeutic vulnerabilities underlying monosomy 7-associated blood remain largely elusive, impeding progress toward improved patient care. The homeostatic cellular requirement for a normal dosage of essential genes creates an opportunity to target that arise due reduced levels proteins encoded by haploinsufficient gene. Briefly, loss one copy dosage-sensitive gene (gene X), combination inhibition itself or related Y), pathway results lethal consequences cells. remarkable selective clinical efficacy lenalidomide treatment del(5q) MDS has demonstrated how allelic haploinsufficiency underlies sensitivity this synthetic lethality. Differential expression analysis protein primary AML samples revealed significant downregulation multiple proteasome members at level, but not RNA level. Primary -7/del(7q) exhibited increased (low IC50) inhibitor bortezomib, as evidenced two independent ex vivo screening cohorts (the Beat FIMM study). Chromosome harbors four subunits, PSMA2, PSMC2, PSMG3, SEM1. We performed expression, number analysis, individual knockout experiments. have PSMA2 be on chromosome 7. confers leukemia growth disadvantage cell clines both TP53 wild-type backgrounds. generated isogenic hemizygous deletion diploid single-cell clones. cells approximately half compared controls, confirming PSMA2hemizygous clones showed significantly enhanced all three evaluated inhibitors (bortezomib, ixazomib, carfilzomib), aligning observed samples. displayed p38 decreased pERK upon inhibitors, potentially contributing their inhibitors. Proteomics validation ongoing. As such, we identified mediated vulnerability further promising approaches treating Citation Format: Haijiao Zhang, Basil Allen, Daniel Bottomly, Peter Ryabinin, Schannon K. Targeting [abstract]. In: Proceedings AACR Special Conference Cancer Research: Expanding Translating Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Ther 2024;23(6 Suppl):Abstract nr A012.