Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia.
| Publication Type | Academic Article |
| Authors | Liu-Lupo Y, Ham J, Jeewajee S, Nguyen L, Delorey T, Ramos A, Weinstock D, Regev A, Hemann M |
| Journal | Blood Cancer J |
| Volume | 13 |
| Issue | 1 |
| Pagination | 92 |
| Date Published | 06/08/2023 |
| ISSN | 2044-5385 |
| Keywords | Multiomics, Leukemia, Lymphoid |
| Abstract | Whole chromosome losses resulting in near-haploid karyotypes are found in a rare subgroup of treatment-refractory acute lymphoblastic leukemia. To systematically dissect the unique physiology and uncover susceptibilities that can be exploited in near-haploid leukemia, we leveraged single-cell RNA-Seq and computational inference of cell cycle stages to pinpoint key differences between near-haploid and diploid leukemia cells. Combining cell cycle stage-specific differential expression with gene essentiality scores from a genome-wide CRISPR-Cas9-mediated knockout screen, we identified the homologous recombination pathway component RAD51B as an essential gene in near-haploid leukemia. DNA damage analyses revealed significantly increased sensitivity of RAD51-mediated repair to RAD51B loss in the G2/M stage of near-haploid cells, suggesting a unique role of RAD51B in the homologous recombination pathway. Elevated G2/M and G1/S checkpoint signaling was part of a RAD51B signature expression program in response to chemotherapy in a xenograft model of human near-haploid B-ALL, and RAD51B and its associated programs were overexpressed in a large panel of near-haploid B-ALL patients. These data highlight a unique genetic dependency on DNA repair machinery in near-haploid leukemia and demarcate RAD51B as a promising candidate for targeted therapy in this treatment-resistant disease. |
| DOI | 10.1038/s41408-023-00863-1 |
| PubMed ID | 37286545 |
| PubMed Central ID | PMC10247733 |