MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Research Abstract Details 

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MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Abstract Text:

Yana Pikman,Benjamin H Lee,Thomas Mercher,Elizabeth McDowell,Benjamin L Ebert,Maricel Gozo,Adam Cuker,Gerlinde Wernig,Sandra Moore,Ilene Galinsky,Daniel J DeAngelo,Jennifer J Clark,Stephanie J Lee,Todd R Golub,Martha Wadleigh,D Gary Gilliland,Ross L Levine,

BACKGROUND: The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). METHODS AND FINDINGS: DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. CONCLUSIONS: Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD.

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Publishing Authors By Initials

Y Pikman,BH Lee,T Mercher,E McDowell,BL Ebert,M Gozo,A Cuker,G Wernig,S Moore,I Galinsky,DJ DeAngelo,JJ Clark,SJ Lee,TR Golub,M Wadleigh,DG Gilliland,RL Levine,

For similar congenital, hereditary, and neonatal diseases and abnormalities: genetic diseases, inborn: metabolism, inborn errors: lipid metabolism, inborn errors: hypolipoproteinemias: hypobetalipoproteinemias: abetalipoproteinemia research abstracts see: congenital, hereditary, and neonatal diseases and abnormalities: genetic diseases, inborn: metabolism, inborn errors: lipid metabolism, inborn errors: hypolipoproteinemias: hypobetalipoproteinemias: abetalipoproteinemia research

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MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: PLoS medicine

VOLUME: 3

Page Numbers: e270

Journal Abbreviation: PLoS Med.

ISSN: 1549-1676

DAY: 3

MONTH: Jul

YEAR: 2006

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101231360

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Keywords Mesh Terms:

KEYWORDS: mRNA Cleavage and Polyadenylation Factor

MESH TERMS: physiology

Chemical & Substance for Abstract: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Information

Substance Name: Receptor, Platelet-Derived Growth Factor

Registry Number: EC 2.7.1.112

Grant and Affiliation Information for MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

AFFILIATION: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Country: United States

AGENCY: United States NIDDK

GRANT: DK50654

ACRONYM: DK

MEDLINETA: PLoS Med

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