Nav: Home

Dual loss of TET proteins prompts lethal upsurge in inflammatory T cells in a mouse model

December 12, 2016

Members of the TET family of proteins help protect against cancer by regulating the chemical state of DNA --and thus turning growth-promoting genes on or off. The latest findings reported by researchers at La Jolla Institute for Allergy and Immunology illustrate just how important TET proteins are in controlling cell proliferation and cell fate.

For the study, published in the December 20, 2016, edition of Nature Immunology, Anjana Rao, PhD, a professor at the La Jolla Institute, genetically engineered mice to lack both TET2 and TET3 in T cells. The mice developed a lethal disease resembling lymphoma within weeks of birth, their spleens and livers bloated with iNKT cells, a normally rare kind of T cell. This finding recapitulated the features of many human blood cancers, including those involving T cells, in which TET2 is often mutated or lost.

"We knew that TET proteins were involved in human cancer but we didn't know how they regulated T cell development," says Angeliki Tsagaratou, Ph.D., an instructor in the Rao lab and the study's first author. "In the new study we saw huge increases in the proliferation of the special iNKT cells in TET2/3 mutant mice. Once growth control was lost, those cells underwent the kind of malignant transformation that gives rise to T cell lymphoma in humans." The results demonstrate how TET proteins serve as anti-cancer factors called tumor suppressors and suggest ways to block malignancy in cancers marked by TET mutations.

Members of the TET family of enzymes help rewrite the epigenome, the regulatory layer of chemical modifications that sits atop the genome and helps determine gene activity without changing the letters of DNA. In addition to the four letters or bases in DNA - A, C, G and T - there is a "fifth base" with a very important role. This base is formed from the DNA base cytosine (C) by addition of a methyl group, and so is called mC (m for methyl). The levels of mC are altered in cancer cells and during the development of embryos.

However, until the discovery of TET proteins in 2009 in the laboratory of Rao, then at Harvard Medical School, it was not known how mC could be converted back to regain C. Dr. Rao's team showed that TET proteins were able to convert 5mC to a sixth base, known as 5hmC. 5hmC is indirectly converted back to C, thus restoring the status quo.

DNA modifications of this type in part govern how compressed and "expressible" a strand is: in general, DNA methylation coils up genes to silence them, while less methylated DNA strands, or strands that possess 5hmC, are more accessible and more likely to be expressed, which means they are directing the synthesis of a particular protein. "When TET proteins are lost, iNKT cells that lack them apparently become trapped in an immature, highly proliferative state," explains Tsagaratou. "Unlike normal cells, they can't switch off growth-promoting genes: they just keep dividing."

DNA sequencing followed by bioinformatic data-crunching revealed the kinds of abnormal DNA methylation patterns typically seen after TET protein loss. That suggested that improper DNA modifications in the TET2/3 mutant T cells allowed unchecked expression of cancer- and inflammation-associated genes. Edahí González-Avalos, one of the two second authors of the study, conducted most of that analysis.

"Without computer analysis of sequencing results, we would not have been able to determine relationships between DNA methylation, how accessible regions of the genome were, global gene expression, or the emergence of cancer cells," says González-Avalos, a graduate student in UCSD's Bioinformatics Graduate Program. "Without computational tools, this study could have taken many, many years!"

A critical test reported in the paper demonstrates how insidious even a few perpetually immature iNKT cells can be. In it, the team transferred a small number of iNKT cells lacking Tet2/3 from mutant mice into adult mice with a robust immune system. But even those mice soon developed lymphoproliferative disease as lethal as that seen in TET2/3 mutant mice.

"We weren't expecting this," says Tsagaratou. "When we transferred mutant cells we thought healthy mice would control their expansion. But in three months mutant cells took over the mouse's immune system and rapidly gave rise to tumors." The lesson of this story? That a functional immune system is no defense against malignancy once deregulated, pro-inflammatory iNKT cells gain a foothold.

In a 2015 Nature Communications paper, Rao, who heads LJI's Division of Signaling and Gene Expression, reported that TET2/3 mutations caused myeloid disease resembling acute myeloid leukemia in mice. The new study extends these findings to a different class of hematological cancers, namely lymphoid cancer, which is caused by abnormal activity of immune T or B cells.

"Right now we don't know how TET mutations specifically contribute to either T cell lymphomas or leukemias. But we think these mutations are early events in both," says Tsagaratou. Thus the search is on is to discover additional cancer-causing genes "downstream" of TET mutations that drive uncontrolled cell division in either context. "Identification of additional factors would give us a broad idea of all steps in pathway and provide multiple targets to hit."
-end-
In addition to Tsagaratou and González-Avalos, Sini Rautio of Aalto University School of Science, in Aalto, Finland, was a co-second author of the paper, contributing significantly to the bioinformatic analysis of genome-wide sequencing data. Also contributing were James Scott Browne, Ph.D., Susan Togher, and William A. Pastor, Ph.D., all from LJI; Ellen V. Rothenberg, Ph.D., of Caltech; and bioinformaticians Lukas Chavez Ph.D., of the German Cancer Research Center in Heidelberg and Harri Lähdesmäki, Ph.D., of Aalto University School of Science, the PhD thesis supervisor of Sini Rautio.

The study was funded by the NIH (R01 grants AI44432, CA151535 and R35CA210043); a Leukemia & Lymphoma Society grant (6187-12, to A.R.); and an Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research grant (to H.L.). Other funding was from the Cancer Research Institute, the Academy of Finland Centre of Excellence in Molecular Systems, Immunology and Physiology Research program, the Damon Runyon Cancer Research Foundation (DRG-2069-11), and the National Science Foundation. doi:10.1038/ni.3630

About La Jolla Institute for Allergy and Immunology

The La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.

La Jolla Institute for Allergy and Immunology

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...