@article{Zohar Sachs_Raha A. Been_Krista J. DeCoursin_Hanh T. Nguyen_Nurul A. Mohd Hassan_Klara E. Noble-Orcutt_Craig E. Eckfeldt_Emily J. Pomeroy_Ernesto Diaz-Flores_Jennifer L. Geurts_Miechaleen D. Diers_Diane E. Hasz_Kelly J. Morgan_Margaret L. MacMillan_Kevin M. Shannon_David A. Largaespada_Stephen M. Wiesner_2016, place={Pavia, Italy}, title={Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency}, volume={101}, url={https://haematologica.org/article/view/7845}, DOI={10.3324/haematol.2015.136002}, abstractNote={Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the <em>NF1</em> gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in <em>NF1</em> 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 <em>via</em> genetic and pharmacological approaches in <em>Nf1</em>-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous <em>Stat5</em> deficiency extended the lifespan of <em>Nf1</em>-deficient mice and eliminated the development of myeloproliferative neoplasm associated with <em>Nf1</em> gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in <em>Nf1</em>-deficient mice. Finally, we found that primary cells from a patient with <em>KRAS</em&gt;-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.}, number={10}, journal={Haematologica}, author={Zohar Sachs and Raha A. Been and Krista J. DeCoursin and Hanh T. Nguyen and Nurul A. Mohd Hassan and Klara E. Noble-Orcutt and Craig E. Eckfeldt and Emily J. Pomeroy and Ernesto Diaz-Flores and Jennifer L. Geurts and Miechaleen D. Diers and Diane E. Hasz and Kelly J. Morgan and Margaret L. MacMillan and Kevin M. Shannon and David A. Largaespada and Stephen M. Wiesner}, year={2016}, month={Sep.}, pages={1190-1199} }