Student and Faculty Publications
Publication Date
5-1-2024
Journal
Cancer Discovery
Abstract
Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.
Keywords
Animals, Humans, Mice, Disease Models, Animal, Hematopoietic Stem Cells, Janus Kinase 2, Mutation, Myeloproliferative Disorders, Signal Transduction
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Neoplasms Commons, Oncology Commons
Comments
PMID: 38230747
Supplementary Materials