Description of a Knock-In Mouse Model of JAK2V617F MPN Emerging from a Minority of Mutated Hematopoietic Stem Cells.

The major weakness of most knock-in JAK2V617F mouse models is the presence of the JAK2 mutation in all rather than in a few hematopoietic stem cells (HSC), like in human "early stage" myeloproliferative neoplasms (MPN). Understanding the mechanisms of disease initiation is critical as underscored by the incidence of clonal hematopoiesis of indeterminate potential associated with JAK2V617F. Currently such studies require competitive transplantation. Here, we report a mouse model obtained by crossing JAK2V617F/WT KI mice with PF4iCre transgenic mice. As expected, PF4iCre;JAK2V617F/WT mice developed an early thrombocytosis due to the expression of JAK2V617F in the megakaryocytes (MK). However, these mice then developed a Polycythemia Vera-like phenotype at 10 week of age. Using mT/mG reporter mice, we demonstrated that Cre recombination was present in all hematopoietic compartments, including in a low number of HSC. The frequency of mutated cells increased along hematopoietic differentiation mimicking the clonal expansion observed in ET and PV patients. This model thus mimics the HSC compartment observed in "early stage" MPN, with a small number of JAK2V617F HSC competing with a majority of JAK2WT HSC. PF4iCre;JAK2V617F/WTmice are a promising tool to investigate the mechanisms that regulate clonal dominance and progression to myelofibrosis.

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