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; ... (2024). Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms. Cancer discovery, 14(5), pp. 737-751. American Association for Cancer Research 10.1158/2159-8290.CD-22-0952
|
Text
cd-22-0952.pdf - Accepted Version Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND). Download (6MB) | Preview |
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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) |
UniBE Contributor: |
Meyer, Sara Christina |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2159-8290 |
Publisher: |
American Association for Cancer Research |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
18 Jan 2024 11:05 |
Last Modified: |
02 May 2024 00:13 |
Publisher DOI: |
10.1158/2159-8290.CD-22-0952 |
PubMed ID: |
38230747 |
BORIS DOI: |
10.48350/191755 |
URI: |
https://boris.unibe.ch/id/eprint/191755 |
Actions (login required)
 |
Edit item |