2. Academic Validation
  3. CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells

CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells

  • Cancer Discov. 2024 May 31. doi: 10.1158/2159-8290.CD-23-1092.
Michael R Waarts 1,  Shoron Mowla 2,  Meaghan Boileau 3,  Anthony R Martinez Benitez 2,  Junya Sango 4,  Maya Bagish 4,  Ines Fernandez-Maestre 2,  Yufan Shan 3,  Shira E Eisman 5,  Young C Park 2,  Matthew Wereski 4,  Isabelle Csete 4,  Kavi O'Connor 6,  Angelica C Romero-Vega 7,  Linde A Miles 8,  Wenbin Xiao 2,  Xiaodi Wu 4,  Richard P Koche 9,  Scott A Armstrong 10,  Alan H Shih 11,  Eirini P Papapetrou 12,  Jason M Butler 13,  Sheng F Cai 2,  Robert L Bowman 14,  Ross L Levine 2
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center, NYC, United States.
  • 2 Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • 3 Dana-Farber Cancer Institute, United States.
  • 4 Memorial Sloan Kettering Cancer Center, United States.
  • 5 Columbia University Medical Center, New York, United States.
  • 6 MSKCC, New York, New York, United States.
  • 7 Memorial Sloan Kettering Cancer Center, New York, New York, United States.
  • 8 Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
  • 9 Memorial Sloan Kettering Cancer Center, New York, United States.
  • 10 Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, United States.
  • 11 Icahn School of Medicine at Mount Sinai, New York, New York, United States.
  • 12 Icahn School of Medicine at Mount Sinai, New York, United States.
  • 13 Weill Cornell Medicine, New York, NY, United States.
  • 14 University of Pennsylvania, Philadelphia, PA, United States.
PMID: 38819218 DOI: 10.1158/2159-8290.CD-23-1092
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.

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