Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms
Short Summary: In this manuscript we developed a reversible JAK2V617F model with Dre->Cre functionality, such that the Cre sites which delete/reverse JAK2V617F are only available after Dre recombination induces mutant expression. This allowed us to test the dependency of JAK2-mutations in propagating myeloproliferative disease.
Abstract: Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation.1 Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele.2 While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients.3, 4 This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles;5 however we hypothesize this is due to the inability 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 Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617Fabrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet26, 7 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.
Recommended citation: Andrew Dunbar, Robert L. Bowman, Young Park, Franco Izzo, Robert M. Myers, Abdul Karzai, Won Jun Kim, Inés Fernández Maestre, Michael R. Waarts, Abbas Nazir, Wenbin Xiao, Max Brodsky, Mirko Farina, Louise Cai, Sheng F. Cai, Benjamin Wang, Wenbin An, Julie L Yang, Shoron Mowla, Shira E. Eisman, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R. Martinez Benitez, Aaron Viny, Richard Koche, Dan A. Landau, Ross L. Levine. Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasm. bioRxiv 2022.05.18.492332; doi: https://doi.org/10.1101/2022.05.18.492332