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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.

journal_name

Haematologica

journal_title

Haematologica

authors

Sachs Z,Been RA,DeCoursin KJ,Nguyen HT,Mohd Hassan NA,Noble-Orcutt KE,Eckfeldt CE,Pomeroy EJ,Diaz-Flores E,Geurts JL,Diers MD,Hasz DE,Morgan KJ,MacMillan ML,Shannon KM,Largaespada DA,Wiesner SM

doi

10.3324/haematol.2015.136002

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

1190-1199

issue

10

eissn

0390-6078

issn

1592-8721

pii

haematol.2015.136002

journal_volume

101

pub_type

杂志文章

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