Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.

DOI
Publisher DOI
PubMed ID
38230747
Abstract
Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPNs), most commonly JAK2V617F. While 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 co-occurring 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.
Date Issued
2024-05-01
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
Dunbar, Andrew J
Bowman, Robert L
Park, Young C
O'Connor, Kavi
Izzo, Franco
Myers, Robert M
Karzai, Abdul
Zaroogian, Zach
Kim, Won Jun
Fernandez-Maestre, Ines
Waarts, Michael R
Nazir, Abbas
Xiao, Wenbin
Codilupi, Tamara
Brodsky, Max
Farina, Mirko
Cai, Louise
Cai, Sheng F
Wang, Benjamin
An, Wenbin
Yang, Julie L
Mowla, Shoron
Eisman, Shira E
Hanasoge Somasundara, Amritha Varshini
Glass, Jacob L
Mishra, Tanmay
Houston, Remie
Guzzardi, Emily
Martinez Benitez, Anthony R
Viny, Aaron D
Koche, Richard P
Landau, Dan A
Levine, Ross L
Additional Credits
Journal
Cancer discovery
Publisher
American Association for Cancer Research
ISSN
2159-8290
Access(Rights)
open.access
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