title: Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms.
abstract: Signaling mutations (eg, JAK2V617F) and mutations in genes involved in epigenetic regulation (eg, TET2) are the most common cooccurring classes of mutations in myeloproliferative neoplasms (MPNs). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPNs such as myelofibrosis and leukemic transformation, suggesting that they may cooperate 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 (HSCs). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and nonoverlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSCs, and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This work provides insight into the functional consequences of JAK2V617F-TET2 comutation in MPNs, particularly as it pertains to HSCs.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Breyfogle
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Emily A
authors.initials: EA
authors.lastname: Rosen
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Luke
authors.initials: L
authors.lastname: Poveromo
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Amy
authors.initials: A
authors.lastname: Ko
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Kristina
authors.initials: K
authors.lastname: Brumme
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY; and.
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Broad Institute, Cambridge, MA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Broad Institute, Cambridge, MA.
authors.forename: Ann
authors.identifier: http://orcid.org/0000-0001-9727-8495
authors.initials: A
authors.lastname: Mullally
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2