In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy.

Publication Type	Academic Article
Authors	Bowman R, Dunbar A, Mishra T, Xiao W, Waarts M, Maestre I, Eisman S, Cai L, Mowla S, Shah N, Youn A, Bennett L, Fontenard S, Gounder S, Gandhi A, Bowman M, O'Connor K, Zaroogian Z, Sánchez-Vela P, Martinez Benitez A, Werewski M, Park Y, Csete I, Krishnan A, Lee D, Boorady N, Potts C, Jenkins M, Cai S, Carroll M, Meyer S, Miles L, Ferrell P, Trowbridge J, Levine R
Journal	Cancer Cell
Volume	42
Issue	11
Pagination	1955-1969.e7
Date Published	11/11/2024
ISSN	1878-3686
Keywords	Mutation, Nucleophosmin, DNA Methyltransferase 3A, Carcinogenesis, fms-Like Tyrosine Kinase 3
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.
DOI	10.1016/j.ccell.2024.10.009
PubMed ID	39532065
PubMed Central ID	PMC11561369