CRISPR dependency screens in primary hematopoietic stem cells identify KDM3B as a genotype-specific vulnerability in IDH2- and TET2-mutant cells Journal Article
| Authors: | Waarts, M. R.; Mowla, S.; Boileau, M.; Martinez Benitez, A. R.; Sango, J.; Bagish, M.; Fernández-Maestre, I.; Shan, Y.; Eisman, S. E.; Park, Y. C.; Wereski, M.; Csete, I.; O'Connor, K.; Romero-Vega, A. C.; Miles, L. A.; Xiao, W.; Wu, X.; Koche, R. P.; Armstrong, S. A.; Shih, A. H.; Papapetrou, E. P.; Butler, J. M.; Cai, S. F.; Bowman, R. L.; Levine, R. L. |
| Article Title: | CRISPR dependency screens in primary hematopoietic stem cells identify KDM3B as a genotype-specific vulnerability in IDH2- and TET2-mutant cells |
| Abstract: | Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs. Significance: Given the broad prevalence, comorbidities, and risk of malignant transformation associated with CH, there is an unmet need to identify therapeutic targets. We develop an ex vivo platform to perform CRISPR/Cas9 screens in primary HSPCs. We identify KDM3B and downstream signaling components as genotype-specific dependencies in CH and myeloid malignancies. See related commentary by Khabusheva and Goodell, p. 1768. ©2024 American Association for Cancer Research. |
| Keywords: | dna binding protein; tet2 protein, human; genetics; mutation; dna-binding proteins; proto-oncogene proteins; mouse; animal; metabolism; animals; mice; genotype; hematopoietic stem cells; hematopoietic stem cell; isocitrate dehydrogenase; histone demethylase; dioxygenase; jumonji domain-containing histone demethylases; humans; human; crispr cas system; crispr-cas systems; proto oncogene protein; dioxygenases; idh2 protein, human |
| Journal Title: | Cancer Discovery |
| Volume: | 14 |
| Issue: | 10 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-10-01 |
| Start Page: | 1860 |
| End Page: | 1878 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-23-1092 |
| PUBMED: | 38819218 |
| PROVIDER: | scopus |
| PMCID: | PMC11452290 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Ross L. Levine -- Source: Scopus |
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