1. Academic Validation
  2. The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

  • Leukemia. 2024 Mar 22. doi: 10.1038/s41375-024-02221-x.
Ali Farrokhi # 1 Tanmaya Atre # 1 Jenna Rever # 1 Mario Fidanza 1 Wendy Duey 2 Samuel Salitra 1 Junia Myung 1 Meiyun Guo 1 Sumin Jo 1 Anuli Uzozie 1 Fatemeh Baharvand 1 Nina Rolf 1 Franziska Auer 3 Julia Hauer 3 Stephan A Grupp 4 Patrice Eydoux 2 Philipp F Lange 1 2 Alix E Seif 4 Christopher A Maxwell 1 5 Gregor S D Reid 6 7
Affiliations

Affiliations

  • 1 Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
  • 2 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 3 Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, Munich, Germany.
  • 4 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
  • 6 Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada. gregor.reid@ubc.ca.
  • 7 Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. gregor.reid@ubc.ca.
  • # Contributed equally.
Abstract

The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eμ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eμ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eμ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.

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