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<meta name="description" content="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 …"><meta name="keywords" content="pmid:25485910, PMC4289115, doi:10.1038/nm.3751, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov&#x27;t, Akinori Yoda, Guillaume Adelmant, Andrew A Lane, Animals, Cell Line, Tumor, Cell Transformation, Neoplastic / genetics*, Drug Resistance, Neoplasm / genetics*, Fusion Proteins, bcr-abl / antagonists &amp; inhibitors, Fusion Proteins, bcr-abl / genetics, GTP-Binding Protein beta Subunits / genetics*, GTP-Binding Protein beta Subunits / metabolism, GTP-Binding Proteins / genetics*, GTP-Binding Proteins / metabolism, Gene Expression Regulation, Neoplastic, Humans, Janus Kinase 2 / biosynthesis, Lymphoma, B-Cell / drug therapy, Lymphoma, B-Cell / genetics*, Lymphoma, B-Cell / pathology, Mice, Mutation, Protein Kinase Inhibitors / therapeutic use, Proto-Oncogene Proteins c-akt / biosynthesis, Proto-Oncogene Proteins c-akt / genetics, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Mutations in G protein β subunits promote transformation and kinase inhibitor resistance - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/25485910/"><meta property="og:description" content="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 …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Mutations in G protein β subunits promote transformation and kinase inhibitor resistance - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/25485910/"><meta name="twitter:description" content="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 …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="9MWiYLhGGS7QFEsUNolnnyl4eaUGopIfqzGnBBK2gtUkz5yKqHYpRGRIMeCSh0gz">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="9MWiYLhGGS7QFEsUNolnnyl4eaUGopIfqzGnBBK2gtUkz5yKqHYpRGRIMeCSh0gz">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="9MWiYLhGGS7QFEsUNolnnyl4eaUGopIfqzGnBBK2gtUkz5yKqHYpRGRIMeCSh0gz">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="9MWiYLhGGS7QFEsUNolnnyl4eaUGopIfqzGnBBK2gtUkz5yKqHYpRGRIMeCSh0gz">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="9MWiYLhGGS7QFEsUNolnnyl4eaUGopIfqzGnBBK2gtUkz5yKqHYpRGRIMeCSh0gz">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="25485910">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1038/nm.3751"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3094&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=25485910&amp;db=pubmed&amp;nlmid=9502015"
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</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/25485910/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=25485910&amp;db=pubmed&amp;nlmid=9502015"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="25485910"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/25485910/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/25485910/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="25485910" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F25485910%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="9MWiYLhGGS7QFEsUNolnnyl4eaUGopIfqzGnBBK2gtUkz5yKqHYpRGRIMeCSh0gz"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
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<h1 class="heading-title">
Mutations in G protein β subunits promote transformation and kinase inhibitor resistance
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Mutations in G protein β subunits promote transformation and kinase inhibitor resistance
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<span class="authors-list-item "><span class="full-name">Akinori Yoda</span><span class="citation-separator">&nbsp;et al.</span></span>
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><sup class="key">1</sup> Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> 1] Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.</li>
<li data-affiliation-id="short-view-affiliation-4"
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><sup class="key">4</sup> Department of Medicine III, Campus Grosshadern, Ludwig-Maximilians-University, and Helmholtz Center, Munich, Germany.</li>
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id="short-view-affiliation-5"
><sup class="key">5</sup> 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Jounce Therapeutics, Inc., Cambridge, Massachusetts, USA.</li>
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id="short-view-affiliation-6"
><sup class="key">6</sup> Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.</li>
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id="short-view-affiliation-7"
><sup class="key">7</sup> Division of Hematology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.</li>
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id="short-view-affiliation-8"
><sup class="key">8</sup> Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.</li>
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><sup class="key">9</sup> Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.</li>
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id="short-view-affiliation-10"
><sup class="key">10</sup> Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.</li>
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id="short-view-affiliation-11"
><sup class="key">11</sup> Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon, USA.</li>
<li data-affiliation-id="short-view-affiliation-12"
id="short-view-affiliation-12"
><sup class="key">12</sup> 1] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Division of Hematology, Brigham and Women&#x27;s Hospital, Boston, Massachusetts, USA.</li>
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id="short-view-affiliation-13"
><sup class="key">13</sup> 1] Division of Hematology, Brigham and Women&#x27;s Hospital, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.</li>
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id="short-view-affiliation-14"
><sup class="key">14</sup> Department of Pathology, Brigham and Women&#x27;s Hospital, Boston, Massachusetts, USA.</li>
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id="short-view-affiliation-15"
><sup class="key">15</sup> 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.</li>
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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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itemprop="associatedMedia"
data-slide-index="0"
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<a class="figure-link"
href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db3d/4289115/18175e01ddcf/nihms-636733-f0001.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-0"
role="button"
data-image-width="502"
data-image-height="686"
data-image-alt="Figure 1"
data-pmc-id="PMC4289115"
data-figure-id="F1">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-0"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db3d/4289115/d0c9bb5a7b49/nihms-636733-f0001.gif"
alt="Figure 1" />
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<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="502">
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<p> Figure 1. Recurrent GNB1 and GNB2 mutations… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1. Recurrent GNB1 and GNB2 mutations confer cytokine-independent growth </p>
</strong>
<div class="figure-caption-contents"><p> (a) Schematic representation of functional… </p></div>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1. Recurrent GNB1 and GNB2 mutations confer cytokine-independent growth
</strong>
<div class="figure-caption-contents">(a) Schematic representation of functional screening using patient-derived cDNA libraries and cytokine-dependent cells. (b) IL3-independent growth of BaF3-MYC cells expressing wild-type (WT) GNB1, GNB1 K89E or empty vector. * p < 0.05 vs wild-type; ** p < 0.01 vs wild-type; p < 0.01 vs empty by t-test; graphs represent mean ± SD of three replicates. (c) Mutations identified in GNB1 and GNB2 in human cancers. Tumor types are indicated for recurrent mutation sites with 3 or more missense alterations. Abbreviations: AML, acute myelogenous leukemia; aCML, atypical chronic myelogenous leukemia; PV, polycythemia vera; MDS, myelodysplastic syndrome; B-ALL, B-cell acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; DLBCL, diffuse large B-cell lymphoma; BPDCN, blastic plasmacytoid dendritic cell neoplasm. (d) Cell counts of IL3-independent BaF3-MYC cells expressing GNB1 and GNB2 alleles or empty vector 14 days after cytokine withdrawal. Data is represented as mutant relative to wild-type for GNB1 or GNB2. * p < 0.05 and ** p < 0.01 vs wild-type by t-test; graphs represent mean ± SD of three replicates. (e) GM-CSF-independent growth of TF-1 cells, as in (d).</div>
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data-image-alt="Figure 2"
data-pmc-id="PMC4289115"
data-figure-id="F2">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db3d/4289115/8347086abd4a/nihms-636733-f0002.gif"
alt="Figure 2" />
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<strong class="figure-label">
<p> Figure 2. Mutant Gβ proteins lose interaction… </p>
</strong>
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<strong class="figure-label">
<p> Figure 2. Mutant Gβ proteins lose interaction with Gα subunits and induce activation of PI3K/AKT/mTOR… </p>
</strong>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2. Mutant Gβ proteins lose interaction with Gα subunits and induce activation of PI3K/AKT/mTOR and MAPK pathways
</strong>
<div class="figure-caption-contents">(a) Molecular representation of a heterotrimeric G protein (Gα: blue, Gβ: red, Gγ: yellow) based on a crystal structure (PDB ID 1GP2; DOI<b>:</b>10.2210/pdb1gp2/pdb). Corresponding sites of multiple recurrent oncogenic mutations are indicated and side chains of the residues are shown in green. (b) Silver staining of anti-Flag immunoprecipitates (IP) from BaF3-MYC cells expressing wild-type GNB1 or GNB1 K89E. The band indicated by the arrow was analyzed by mass spectrometry and the three Gα subunits indicated were identified. (c) Unsupervised clustering analysis of proteins identified in TAP-MS analyses of GNB1, based on their relative association to wild-type and mutant GNB1. Combined extracts of SILAC-labeled TF-1 cells (Heavy: TF-1-Flag-HA-GNB1 mutants, Light: TF-1-Flag-HA-GNB1 WT) were used for tandem affinity purification (TAP) with Flag and HA antibodies followed by mass spectrometry. The ratio of wild type and mutant GNB1 in each TAP was used to normalize the abundance of all interacting proteins. Normalized abundance of G protein subunits and PDCL associated with mutant compared to wild type GNB1 is shown (red = more binding to mutant, blue = less binding to mutant compared to wild-type). (d) Western blotting of anti-Flag IP and whole cell lysates (WCL) from BaF3-MYC cells expressing Gβ alleles. (e) GSEA plots of the indicated gene sets in TF-1 cells transduced with GNB1 K89E that were isolated 12 hours after GM-CSF withdrawal (K89E starved, n = 3) compared to the combined data from TF-1 cells transduced with empty vector that were isolated after GM-CSF withdrawal (n = 3) and either cell line without cytokine withdrawal (n = 3 each; total of n = 9 controls). (f) Heatmap of leading edge genes in the AKT gene set from gene set enrichment analysis in TF-1 GNB1 K89E or empty vector-transduced cells with (+) or without () cytokine starvation. (g) Western blotting of TF-1 cells expressing GNB1 alleles or empty vector.</div>
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itemprop="contentUrl"
aria-describedby="figure-caption-2"
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data-image-height="453"
data-image-alt="Figure 3"
data-pmc-id="PMC4289115"
data-figure-id="F3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db3d/4289115/8ad72b8a669c/nihms-636733-f0003.gif"
alt="Figure 3" />
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<strong class="figure-label">
<p> Figure 3. GNB1 mutants promote myeloid dendritic… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3. GNB1 mutants promote myeloid dendritic cell neoplasms <i> in vivo </i> </p>
</strong>
<div class="figure-caption-contents"><p> (a) Survival of recipient… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 3. GNB1 mutants promote myeloid dendritic cell neoplasms <i>in vivo</i>
</strong>
<div class="figure-caption-contents">(a) Survival of recipient mice after transplantation of 5-FU-treated <i>Cdkn2a</i><sup>/</sup> bone marrow (BM) transduced with GNB1 alleles or empty vector (n = 20 mice/group for GNB1 K89E or WT, n = 10 mice/group for others; * p = 0.048 vs empty, *** p &lt; 0.0001 vs empty, curves compared by log-rank test). (b) Representative flow cytometry of neoplastic cells from spleens of GNB1 K89E recipients from panel A. (c) Western blotting of K562 cells expressing GNB1 or GNB1 K89E. Cells were starved of serum two hours followed by drug treatment (BEZ235 300 nM, AZD8055 300 nM, Rapamycin 10 nM, U0126 10 μM) for two hours. (d) Survival of recipient mice after secondary transplantation of splenocytes from mice in the GNB1 K89E group in panel A. Mice transplanted with two separate malignancies were treated with BEZ235 or vehicle from day 1031 after transplantation (n = 6 mice/group; * p &lt; 0.05 vs vehicle, curves compared by log-rank test). (e) Western blotting of splenocytes from secondary recipients of malignancies from panel A treated with DMSO or vehicle. Beginning 10 days after transplantation, recipient mice were treated with vehicle or BEZ235 for 3 days (1023) or 16 days (1026).</div>
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data-figure-id="F4">
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<p> Figure 4. GNB1/2 mutations confer resistance to… </p>
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<p> Figure 4. GNB1/2 mutations confer resistance to kinase inhibitors </p>
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<div class="figure-caption-contents"><p> (a) Dose-response of A375 cells transduced… </p></div>
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Figure 4. GNB1/2 mutations confer resistance to kinase inhibitors
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<div class="figure-caption-contents">(a) Dose-response of A375 cells transduced with GNB2, GNB2 K78E or empty vector and treated with vemurafenib for 48 hours. PC9 cells, which do not harbor a BRAF mutation, were used as a negative control for vemurafenib sensitivity. Data normalized to DMSO only and to maximal response in empty vector. ** p < 0.01 for pairwise comparison between GNB mutant and wild-type at a given dose level by t-test; graphs represent mean ± SD of three replicates. (b) Western blotting of K562 cells transduced with wild-type GNB1, GNB1 K89E or empty vector. Cells were starved of serum for two hours followed by two hours of drug treatment (C: control DMSO, N: nilotinib 100 nM, Be: BEZ235 300 nM, I: imatinib 1000 nM). (c) Dose-response of K562 cells transduced with GNB1, GNB1 K89E or empty vector and treated with nilotinib for 48 hours, analyzed as in panel (a). (d) Growth of BaF3-Myc cells transduced with BCR-ABL in combination with GNB1, GNB1 K89E or empty vector and cultured in the presence of nilotinib (100 nM). * p < 0.05 and ** p < 0.01 vs wild-type; p < 0.01 vs empty by t-test; graphs represent mean ± SD of three replicates. (e) Dose-response of SET2 cells transduced with GNB1, GNB1 K89E or empty vector and treated with ruxolitinib for 48 hours, analyzed as in panel (a). (f) Growth of SET2 cells transduced with GNB1, GNB1 K89E or empty vector and cultured in the presence of ruxolitinib (1 μM), analyzed as in panel (d). (g) Growth of BaF3-Myc cells transduced with MPL P440L in combination with GNB1, GNB1 K89E or empty vector and cultured in the presence of ruxolitinib (1 μM), analyzed as in panel (d).</div>
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