2. Academic Validation
  3. In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy

In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy

  • Cancer Cell. 2024 Nov 11;42(11):1955-1969.e7. doi: 10.1016/j.ccell.2024.10.009.
Robert L Bowman 1,  Andrew J Dunbar 2,  Tanmay Mishra 3,  Wenbin Xiao 4,  Michael R Waarts 5,  Inés Fernández Maestre 5,  Shira E Eisman 3,  Louise Cai 3,  Shoron Mowla 3,  Nisargbhai Shah 6,  Angela Youn 6,  Laura Bennett 7,  Suean Fontenard 7,  Shreeya Gounder 6,  Anushka Gandhi 6,  Michael Bowman 6,  Kavi O'Connor 3,  Zachary Zaroogian 3,  Pablo Sánchez-Vela 3,  Anthony R Martinez Benitez 3,  Matthew Werewski 3,  Young Park 3,  Isabelle S Csete 3,  Aishwarya Krishnan 3,  Darren Lee 3,  Nayla Boorady 3,  Chad R Potts 8,  Matthew T Jenkins 8,  Sheng F Cai 2,  Martin P Carroll 9,  Sara E Meyer 10,  Linde A Miles 3,  P Brent Ferrell Jr 8,  Jennifer J Trowbridge 11,  Ross L Levine 12
Affiliations

Affiliations

  • 1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Cancer Biology, Perelman Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: robert.bowman@pennmedicine.upenn.edu.
  • 2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6 Department of Cancer Biology, Perelman Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Department of Cell and Developmental Biology, Perelman Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37212 USA.
  • 9 Department of Medicine, Perelman Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 10 Department of Cancer Biology, Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
  • 11 The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • 12 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: leviner@mskcc.org.
PMID: 39532065 DOI: 10.1016/j.ccell.2024.10.009
Abstract

Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA Sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes. Here, we integrate multi-recombinase tools for reversible, sequential mutagenesis from premalignancy to leukemia. We demonstrate that inducible FLT3 mutations differentially cooperate with Dnmt3a, IDH2, and Npm1 mutant alleles, and that changing the order of mutations influences cellular and transcriptional landscapes. We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution.

Keywords

genetically engineered mouse models; leukemia; oncogene dependency; sequential mutagenesis.

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