Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia

Near-haploid karyotypes, characterized by whole chromosome losses, are observed in a rare subgroup of treatment-refractory acute lymphoblastic leukemia (ALL). This study utilizes single-cell RNA sequencing and computational inference of cell cycle stages to identify key differences between near-haploid and diploid leukemia cells. The homologous recombination pathway component RAD51B is identified as an essential gene in near-haploid leukemia. Increased sensitivity to RAD51-mediated repair upon RAD51B loss in the G2/M stage of near-haploid cells is observed. Elevated G2/M and G1/S checkpoint signaling is part of a RAD51B signature expression program in response to chemotherapy in a xenograft model and is overexpressed in near-haploid B-ALL patients. These findings highlight a unique genetic dependency on DNA repair machinery in near-haploid leukemia, proposing RAD51B as a potential therapeutic target.

Yunpeng Liu-Lupo, James Dongjoo Ham, Swarna K. A. Jeewajee, Lan Nguyen, Toni Delorey, Azucena Ramos, David M. Weinstock, Aviv Regev, Michael T. Hemann