Jak2^V617F Reversible Activation Shows an Essential Requirement for Jak2^V617F in Myeloproliferative Neoplasms

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 JAK2^V617F 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 Jak2^V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2^V617Fabrogates 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 Jak2^V617F in MPN cells with antecedent loss of Tet2^{6, 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 JAK2^V617F represents the best therapeutic approach for JAK2^V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.