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Integrated single-cell transcriptomics and functional genomics reveal RAD51B as an essential gene in near-haploid leukemia

ABSTRACT: Integrated single-cell transcriptomics and functional genomics reveal RAD51B as an essential gene in near-haploid leukemia

PROVIDER: PRJNA828194 | ENA |

REPOSITORIES: ENA

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Integrated single-cell transcriptomics and functional genomics reveal RAD51B as an essential gene in near-haploid leukemia

Project description: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 transcriptomics 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 metrics obtained 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. We observed elevated G2/M checkpoint signaling as well as a RAD51B signature expression program in response to chemotherapy in a xenograft model of human near-haploid B-ALL, as well as overexpression of RAD51B and its associated programs 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.

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