Supplementary Figure S6 from Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms

Dunbar, Andrew J.; Bowman, Robert L.; Park, Young C.; O'Connor, Kavi; Izzo, Franco; Myers, Robert M.; Karzai, Abdul; Zaroogian, Zachary; Kim, Won Jun; Fernández-Maestre, Inés; 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.; Meyer, Sara C.; Landau, Dan A.; Levine, Ross L.

doi:10.1158/2159-8290.25728915.v1

cd-22-0952_supplementary_figure_s6_suppsf6.pdf (931.4 kB)

Supplementary Figure S6 from Jak2^V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms

journal contribution

posted on 2024-05-01, 07:40 authored by Andrew J. Dunbar, Robert L. Bowman, Young C. Park, Kavi O'Connor, Franco Izzo, Robert M. Myers, Abdul Karzai, Zachary Zaroogian, Won Jun Kim, Inés Fernández-Maestre, Michael R. Waarts, Abbas Nazir, Wenbin Xiao, Tamara Codilupi, Max Brodsky, Mirko Farina, Louise Cai, Sheng F. Cai, Benjamin Wang, Wenbin An, Julie L. Yang, Shoron Mowla, Shira E. Eisman, Amritha Varshini Hanasoge Somasundara, Jacob L. Glass, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R. Martinez Benitez, Aaron D. Viny, Richard P. Koche, Sara C. Meyer, Dan A. Landau, Ross L. Levine

Acute phenotypic and transcriptional changes following Jak2V617F reversion

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Leukemia and Lymphoma Society (LLS)

Damon Runyon Cancer Research Foundation (DRCRF)

National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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National Heart, Lung, and Blood Institute (NHLBI)

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ARTICLE 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. Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy.See related commentary by Celik and Challen, p. 701.This article is featured in Selected Articles from This Issue, p. 695

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Keywords

Hematological Cancers Leukemias Oncogenes & Tumor Suppressors Oncogenes Preclinical Models Animal models of cancer

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