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.
Competing Interest Statement
R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Bakx, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics and Isoplexis. He has received research support from Abbvie, Constellation, Ajax, Zentalis and Prelude. He has received research support from and consulted for Celgene and Roche and has consulted for Syndax, Incyte, Janssen, Astellas, Morphosys and Novartis. He has received honoraria from Astra Zeneca and Novartis for invited lectures and from Gilead and Novartis for grant reviews. D.A.L. has served as a consultant for Abbvie and Illumina and is on the Scientific Advisory Board of Mission Bio and C2i Genomics. D.A.L. has received prior research funding from BMS, 10X Genomics and Illumina unrelated to the current manuscript. S.F.C. is a consultant for and holds equity interest in Imago Biosciences. R.L.B. has received honoraria from Mission Bio and is a member of the Speakers Bureau for Mission Bio. No other authors report competing interests.