Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

News in Brief

Studies Identify Non-Hodgkin Lymphoma Suppressor

DOI: 10.1158/2159-8290.CD-NB2015-141 Published December 2015
  • Article
  • Info & Metrics
Loading

Although the gene for KMT2D, a histone methyltransferase, is frequently mutated in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL)—the most common types of non-Hodgkin lymphoma—just how this influences tumorigenesis has been obscure. Two simultaneously published studies shed light on this matter: KMT2D, also known as MLL2 or MLL4, is a bona fide tumor suppressor, and its loss of function through genetic changes promotes malignancy.

Most KMT2D mutations are of the truncating, or nonsense, variety, generating a protein that lacks its enzymatic domain. A study from Columbia University in New York, NY, showed that KMT2D can also be inactivated through missense mutations, and that in a small subset of cases, despite an intact gene, the protein is never expressed. KMT2D is responsible for methylating lysine 4 on histone 3 (H3K4), “an epigenetic mark that signals chromatin accessibility and transcriptional activation,” explains senior author Laura Pasqualucci, MD, an associate professor of pathology. “We figured that KMT2D deficiency somehow subverts the epigenetic landscape of B cells to one favoring malignant transformation.”

Pasqualucci and her team created two mouse models that recapitulated different stages of B-cell development: before and after the initiation of germinal centers (GC), sites where B cells proliferate and mature to produce antibodies during a normal immune response. In mice in which the GC reaction had already started, B cells were unaffected by KMT2D deletion and developed normally. However, early removal of KMT2D, before GC initiation, caused mice to display more and larger-sized GCs with higher than usual rates of B-cell proliferation. Transcriptionally, these GCs were also enriched in genes favoring resistance to apoptosis—in all, “a dangerous, potentially tumorigenic environment,” Pasqualucci notes.

In an independent study from Memorial Sloan Kettering Cancer Center (MSKCC) and Weill Cornell Medical College, both in New York, NY, researchers showed that FL incidence rose from 30% to 60% upon KMT2D deletion in mice with a deregulated oncogene, BCL2. (Pasqualucci's team also noted cooperation between deregulated BCL2 and KMT2D loss in increasing lymphoma development, albeit in a different mouse model.) The MSKCC and Weill Cornell researchers then compared gene expression data from human and mouse FL tumors, searching for changes sparked by mutant KMT2D.

“We found that similar genes were downregulated in both humans and mice, including established tumor suppressors like TNFAIP3 and SOCS3,” says Hans-Guido Wendel, MD, a cancer biologist at MSKCC and one of the study's senior authors. Further analyses revealed that these genes are direct targets of KMT2D, with their downregulation driven by mutant-KMT2D–induced loss of H3K4 methylation at enhancer or promoter regions, or both.

“We think we're off to a good start in answering the question ‘What are KMT2D's targets, and what does its loss of function do?'” Wendel says. He and Pasqualucci consider their studies parallel investigations that document KMT2D's previously unknown tumor-suppressor role in lymphoid malignancies. Pasqualucci also notes that KMT2D lesions are likely among the earliest acquired by B cells en route to malignant transformation.

Although Wendel's group observed that in DLBCL treated with standard chemotherapy, KMT2D mutations did not affect outcomes like overall or progression-free survival, whether this mutation status could influence the efficacy of newer targeted therapies remains an open question, he says. Meanwhile, inhibiting enzymes like JARID1 and LSD1, which normally demethylate H3K4, may present another therapeutic option for KMT2D-deficient lymphomas.

“The idea is that this could rebalance the methylation landscape,” Wendel explains, “and it's one we're exploring more closely.”

  • ©2015 American Association for Cancer Research.
PreviousNext
Back to top
Cancer Discovery: 5 (12)
December 2015
Volume 5, Issue 12
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover

Sign up for alerts

View this article with LENS

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Discovery article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Studies Identify Non-Hodgkin Lymphoma Suppressor
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Studies Identify Non-Hodgkin Lymphoma Suppressor
Cancer Discov December 1 2015 (5) (12) OF6; DOI: 10.1158/2159-8290.CD-NB2015-141

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Studies Identify Non-Hodgkin Lymphoma Suppressor
Cancer Discov December 1 2015 (5) (12) OF6; DOI: 10.1158/2159-8290.CD-NB2015-141
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • ADC Successfully Targets Urothelial Cancer
  • Break Through Cancer Launches with $250M Pledge
  • By The Numbers: Novel Drugs Approved by the FDA, 2011-2020
Show more News in Brief
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement