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

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 pathogeneti...

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Main Authors: 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
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2006-07-01
Series:PLoS Medicine
Online Access:http://europepmc.org/articles/PMC1502153?pdf=render
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author 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
author_facet 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
author_sort Yana Pikman
collection DOAJ
description 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).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.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.
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spelling doaj.art-41e9292b1f724c7da3d9525fa803db032022-12-21T18:20:05ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762006-07-0137e27010.1371/journal.pmed.0030270MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.Yana PikmanBenjamin H LeeThomas MercherElizabeth McDowellBenjamin L EbertMaricel GozoAdam CukerGerlinde WernigSandra MooreIlene GalinskyDaniel J DeAngeloJennifer J ClarkStephanie J LeeTodd R GolubMartha WadleighD Gary GillilandRoss L LevineThe 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).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.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.http://europepmc.org/articles/PMC1502153?pdf=render
spellingShingle 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
MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
PLoS Medicine
title MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
title_full MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
title_fullStr MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
title_full_unstemmed MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
title_short MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
title_sort mplw515l is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia
url http://europepmc.org/articles/PMC1502153?pdf=render
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