Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice combine to promote disease progression in myeloproliferative neoplasms
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une délétion du gène Tet2 et la mutation V617F du gène Jak2 favorisent la progression d'une néoplasie myéloproliférative et la transformation leucémique
Signaling mutations (e.g. JAK2V617F) and mutations in genes involved in epigenetic regulation (e.g. TET2) are the most common co-occurring classes of mutations in myeloproliferative neoplasms (MPN). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPN such as myelofibrosis and leukemic transformation, suggesting that they may co-operate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSC). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and non-overlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSC and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This works provides insights into the functional consequences of JAK2V617F-TET2 co-mutation in MPN, particularly as it pertains to HSC.