Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency.
Autor: | Sachs Z; 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., Been RA; 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., DeCoursin KJ; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Nguyen HT; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Mohd Hassan NA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Noble-Orcutt KE; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Eckfeldt CE; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Pomeroy EJ; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA., Diaz-Flores E; Department of Pediatrics, University of California, San Francisco, CA, USA Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA., Geurts JL; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Diers MD; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Hasz DE; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Morgan KJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., MacMillan ML; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, MN, USA., Shannon KM; Department of Pediatrics, University of California, San Francisco, CA, USA Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA., Largaespada DA; 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., Wiesner SM; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA Center for Allied Health Programs, University of Minnesota, Minneapolis, MN, USA. |
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Jazyk: | angličtina |
Zdroj: | Haematologica [Haematologica] 2016 Oct; Vol. 101 (10), pp. 1190-1199. Date of Electronic Publication: 2016 Jul 14. |
DOI: | 10.3324/haematol.2015.136002 |
Abstrakt: | 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. (Copyright© Ferrata Storti Foundation.) |
Databáze: | MEDLINE |
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