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Yoda, A.* ; Adelmant, G.* ; Tamburini, J.* ; Chapuy, B.* ; Shindoh, N.* ; Yoda, Y.* ; Weigert, O. ; Kopp, N.* ; Wu, S.C.* ; Kim, S.S.* ; Liu, H.* ; Tivey, T.* ; Christie, A.L.* ; Elpek, K.G.* ; Card, J.* ; Gritsman, K.* ; Gotlib, J.* ; Deininger, M.W.* ; Makishima, H.* ; Turley, S.J.* ; Javidi-Sharifi, N.* ; Maciejewski, J.P.* ; Jaiswal, S.* ; Ebert, B.L.* ; Rodig, S.J.* ; Tyner, J.W.* ; Marto, J.A.* ; Weinstock, D.M.* ; Lane, A.A.*

Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.

J. Nat. Med. 21, 71-75 (2015)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Acute Lymphoblastic-leukemia; Dendritic Cell Neoplasm; Gamma-subunits; Myelodysplastic Syndromes; Coupled Receptors; Genome; Cancer; Activation; Landscape; Melanoma
Sprache englisch
Veröffentlichungsjahr 2015
Prepublished im Jahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 1340-3443
e-ISSN 1861-0293
Zeitschrift Journal of natural medicines
Quellenangaben Band: 21, Heft: 1, Seiten: 71-75 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Tokyo [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-521000-001
PubMed ID 25485910
DOI 10.1038/nm.3751
WOS ID WOS:000348408000015
Erfassungsdatum 2014-12-10
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