title: Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency.
abstract: Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the NF1 gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in NF1 and have a 200- to 500-fold increased risk of juvenile myelomonocytic leukemia. Leukemia cells from patients with juvenile myelomonocytic leukemia display hypersensitivity to certain cytokines, such as granulocyte-macrophage colony-stimulating factor. The granulocyte-macrophage colony-stimulating factor receptor utilizes pre-associated JAK2 to initiate signals after ligand binding. JAK2 subsequently activates STAT5, among other downstream effectors. Although STAT5 is gaining recognition as an important mediator of growth factor signaling in myeloid leukemias, the contribution of STAT5 to the development of hyperactive RAS-initiated myeloproliferative disease has not been well described. In this study, we investigated the consequence of STAT5 attenuation via genetic and pharmacological approaches in Nf1-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous Stat5 deficiency extended the lifespan of Nf1-deficient mice and eliminated the development of myeloproliferative neoplasm associated with Nf1 gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in Nf1-deficient mice. Finally, we found that primary cells from a patient with KRAS-mutant juvenile myelomonocytic leukemia displayed reduced colony formation in response to JAK2 inhibition. Our findings establish a central role for STAT5 activation in the pathogenesis of juvenile myelomonocytic leukemia and suggest that targeting this pathway may be of clinical utility in these patients.
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA sachs038@umn.edu.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Sachs
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA College of Veterinary Medicine and Department of Comparative and Molecular Biosciences, University of Minnesota, St. Paul, MN, USA.
authors.forename: Raha A
authors.initials: RA
authors.lastname: Been
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Krista J
authors.initials: KJ
authors.lastname: DeCoursin
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Hanh T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Nurul A
authors.initials: NA
authors.lastname: Mohd Hassan
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Klara E
authors.initials: KE
authors.lastname: Noble-Orcutt
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Eckfeldt
authors.affiliation: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Pomeroy
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA, USA Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Flores
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Geurts
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Miechaleen D
authors.initials: MD
authors.lastname: Diers
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Hasz
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Morgan
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: MacMillan
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA, USA Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shannon
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, MN, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA Center for Allied Health Programs, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Wiesner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics; D054429:Leukemia, Myelomonocytic, Juvenile / Q000209:etiology* / Q000235:genetics; D051379:Mice; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D025542:Neurofibromin 1 / Q000172:deficiency*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D025542:Neurofibromin 1; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D016283:Proto-Oncogene Proteins p21(ras)