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| Status |
Public on Dec 07, 2014 |
| Title |
Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Activating mutations of G protein alpha subunits (Ga) occur in 4-5% of all human cancers1 but oncogenic alterations in beta subunits (Gb) have not been defined. Here we demonstrate that recurrent mutations in the Gb proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Ga subunits as well as downstream effectors, and disrupt Ga-Gbg interactions. Different mutations in Gb proteins clustered to some extent based on lineage; for example, all eleven GNB1 K57 mutations were in myeloid neoplasms while 6 of 7 GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 alleles in Cdkn2a-deficient 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, GNB1 mutations co-occurred with oncogenic kinase alterations, including BCR/ABL, JAK2 V617F and BRAF V600K. Co-expression of patient-derived GNB1 alleles with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 mutations 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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| Overall design |
The GM-CSF dependent human cell line TF-1 was transduced with a retrovirus expressing GNB1 K89E or empty vector. RNA was extracted from cells 12 hours after withdrawal of GM-CSF and from cells maintained in GM-CSF. Biological triplicates of each condition were performed. Gene expression differences were calculated between the four conditions.
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| Contributor(s) |
Yoda A, Chapuy B, Lane AA |
| Citation(s) |
25485910 |
| |
| Submission date |
Sep 02, 2014 |
| Last update date |
Jan 06, 2017 |
| Contact name |
Andrew Lane |
| E-mail(s) |
aalane@partners.org
|
| Phone |
617-632-4589
|
| Organization name |
Dana-Farber Cancer Institute
|
| Street address |
450 Brookline Ave
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19145 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [CDF: hugene10st_Hs_ENSG_16.0.0] |
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| Samples (12)
|
| GSM1495283 |
TF-pMSCVpuro-Cytokine withdrawl-replicate 1 |
| GSM1495284 |
TF-pMSCVpuro-Cytokine withdrawl-replicate 2 |
| GSM1495285 |
TF-pMSCVpuro-Cytokine withdrawl-replicate 3 |
| GSM1495286 |
TF-pMSCVpuro-GNB1K89E-Cytokine withdrawl-replicate 1 |
| GSM1495287 |
TF-pMSCVpuro-GNB1K89E-Cytokine withdrawl-replicate 2 |
| GSM1495288 |
TF-pMSCVpuro-GNB1K89E-Cytokine withdrawl-replicate 3 |
| GSM1495289 |
TF-pMSCVpuro-no Cytokine withdrawl-replicate 1 |
| GSM1495290 |
TF-pMSCVpuro-no Cytokine withdrawl-replicate 2 |
| GSM1495291 |
TF-pMSCVpuro-no Cytokine withdrawl-replicate 3 |
| GSM1495292 |
TF-pMSCVpuro-GNB1K89E-no Cytokine withdrawl-replicate 1 |
| GSM1495293 |
TF-pMSCVpuro-GNB1K89E-no Cytokine withdrawl-replicate 2 |
| GSM1495294 |
TF-pMSCVpuro-GNB1K89E-no Cytokine withdrawl-replicate 3 |
|
| Relations |
| BioProject |
PRJNA260048 |
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