CRISPR-Cas9 Library Screening Identifies Novel Molecular Vulnerabilities in KMT2A-Rearranged Acute Lymphoblastic Leukemia

Pauline Schneider, Priscilla Wander, Susan T C J M Arentsen-Peters, Kirsten S Vrenken, Dedeke Rockx-Brouwer, Fabienne R S Adriaanse, Veerle Hoeve, Irene Paassen, Jarno Drost, Rob Pieters, Ronald W Stam

Research output: Contribution to journalArticlepeer-review


In acute lymphoblastic leukemia (ALL), chromosomal translocations involving the KMT2A gene represent highly unfavorable prognostic factors and most commonly occur in patients less than 1 year of age. Rearrangements of the KMT2A gene drive epigenetic changes that lead to aberrant gene expression profiles that strongly favor leukemia development. Apart from this genetic lesion, the mutational landscape of KMT2A-rearranged ALL is remarkably silent, providing limited insights for the development of targeted therapy. Consequently, identifying potential therapeutic targets often relies on differential gene expression, yet the inhibition of these genes has rarely translated into successful therapeutic strategies. Therefore, we performed CRISPR-Cas9 knock-out screens to search for genetic dependencies in KMT2A-rearranged ALL. We utilized small-guide RNA libraries directed against the entire human epigenome and kinome in various KMT2A-rearranged ALL, as well as wild-type KMT2A ALL cell line models. This screening approach led to the discovery of the epigenetic regulators ARID4B and MBD3, as well as the receptor kinase BMPR2 as novel molecular vulnerabilities and attractive therapeutic targets in KMT2A-rearranged ALL.

Original languageEnglish
JournalInternational journal of molecular sciences
Issue number17
Publication statusPublished - Jan 2023


  • Humans
  • CRISPR-Cas Systems
  • Gene Library
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Transcription Factors
  • Cell Line
  • Antigens, Neoplasm
  • Neoplasm Proteins


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