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Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia
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-Se...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10247733/ https://www.ncbi.nlm.nih.gov/pubmed/37286545 http://dx.doi.org/10.1038/s41408-023-00863-1 |
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author | Liu-Lupo, Yunpeng Ham, James Dongjoo Jeewajee, Swarna K. A. Nguyen, Lan Delorey, Toni Ramos, Azucena Weinstock, David M. Regev, Aviv Hemann, Michael T. |
author_facet | Liu-Lupo, Yunpeng Ham, James Dongjoo Jeewajee, Swarna K. A. Nguyen, Lan Delorey, Toni Ramos, Azucena Weinstock, David M. Regev, Aviv Hemann, Michael T. |
author_sort | Liu-Lupo, Yunpeng |
collection | PubMed |
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 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. |
format | Online Article Text |
id | pubmed-10247733 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-102477332023-06-09 Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia Liu-Lupo, Yunpeng Ham, James Dongjoo Jeewajee, Swarna K. A. Nguyen, Lan Delorey, Toni Ramos, Azucena Weinstock, David M. Regev, Aviv Hemann, Michael T. Blood Cancer J Article 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. Nature Publishing Group UK 2023-06-08 /pmc/articles/PMC10247733/ /pubmed/37286545 http://dx.doi.org/10.1038/s41408-023-00863-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liu-Lupo, Yunpeng Ham, James Dongjoo Jeewajee, Swarna K. A. Nguyen, Lan Delorey, Toni Ramos, Azucena Weinstock, David M. Regev, Aviv Hemann, Michael T. Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia |
title | Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia |
title_full | Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia |
title_fullStr | Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia |
title_full_unstemmed | Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia |
title_short | Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia |
title_sort | integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10247733/ https://www.ncbi.nlm.nih.gov/pubmed/37286545 http://dx.doi.org/10.1038/s41408-023-00863-1 |
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