Michael R Waarts, Shoron Mowla, Meaghan Boileau, Anthony R Martinez Benitez, Junya Sango, Maya Bagish, Inés Fernández-Maestre, Yufan Shan, Shira E Eisman, Young C Park, Matthew Wereski, Isabelle Csete, Kavi O'Connor, Angelica C Romero-Vega, Linde A Miles, Wenbin Xiao, Xiaodi Wu, Richard P Koche, Scott A Armstrong, Alan H Shih, Eirini P Papapetrou, Jason M Butler, Sheng F Cai, Robert L Bowman, Ross L Levine
{"title":"原代造血干细胞的 CRISPR 依赖性筛选确定了 KDM3B 在 IDH2- 和 TET2 突变细胞中的基因型特异性弱点。","authors":"Michael R Waarts, Shoron Mowla, Meaghan Boileau, Anthony R Martinez Benitez, Junya Sango, Maya Bagish, Inés Fernández-Maestre, Yufan Shan, Shira E Eisman, Young C Park, Matthew Wereski, Isabelle Csete, Kavi O'Connor, Angelica C Romero-Vega, Linde A Miles, Wenbin Xiao, Xiaodi Wu, Richard P Koche, Scott A Armstrong, Alan H Shih, Eirini P Papapetrou, Jason M Butler, Sheng F Cai, Robert L Bowman, Ross L Levine","doi":"10.1158/2159-8290.CD-23-1092","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1860-1878"},"PeriodicalIF":29.7000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452290/pdf/","citationCount":"0","resultStr":"{\"title\":\"CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype-specific Vulnerability in IDH2- and TET2-mutant Cells.\",\"authors\":\"Michael R Waarts, Shoron Mowla, Meaghan Boileau, Anthony R Martinez Benitez, Junya Sango, Maya Bagish, Inés Fernández-Maestre, Yufan Shan, Shira E Eisman, Young C Park, Matthew Wereski, Isabelle Csete, Kavi O'Connor, Angelica C Romero-Vega, Linde A Miles, Wenbin Xiao, Xiaodi Wu, Richard P Koche, Scott A Armstrong, Alan H Shih, Eirini P Papapetrou, Jason M Butler, Sheng F Cai, Robert L Bowman, Ross L Levine\",\"doi\":\"10.1158/2159-8290.CD-23-1092\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":9430,\"journal\":{\"name\":\"Cancer discovery\",\"volume\":\" \",\"pages\":\"1860-1878\"},\"PeriodicalIF\":29.7000,\"publicationDate\":\"2024-10-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452290/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer discovery\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/2159-8290.CD-23-1092\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-23-1092","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype-specific Vulnerability in IDH2- and TET2-mutant Cells.
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.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.