title: Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera.
abstract: Interferon-α (IFNα) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFNα reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNα on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNα on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNα treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNα treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNα on Jak2V617F mutant and normal hematopoiesis and suggest that IFNα achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNα and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. amullally@partners.org
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.forename: Claudia
authors.initials: C
authors.lastname: Bruedigam
authors.forename: Luke
authors.initials: L
authors.lastname: Poveromo
authors.forename: Florian H
authors.initials: FH
authors.lastname: Heidel
authors.forename: Amy
authors.initials: A
authors.lastname: Purdon
authors.forename: Therese
authors.initials: T
authors.lastname: Vu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Austin
authors.forename: Dirk
authors.initials: D
authors.lastname: Heckl
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Breyfogle
authors.forename: Catherine Paine
authors.initials: CP
authors.lastname: Kuhn
authors.forename: Demetrios
authors.initials: D
authors.lastname: Kalaitzidis
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Geoff R
authors.initials: GR
authors.lastname: Hill
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019337:Hematologic Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D010649:Phenylalanine / Q000235:genetics; D011087:Polycythemia Vera / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014633:Valine / Q000235:genetics
chemical_list: D016898:Interferon-alpha; D050505:Mutant Proteins; D010649:Phenylalanine; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D014633:Valine