Glitch in genome architecture may cause B-cell malignancies

February 01, 2021

NEW YORK, NY (Feb. 1, 2021)--Errors in the way chromosomes are packed into antibody-producing B cells appear to play a role in the development of B cell-related blood cancers, according to a new study by researchers at Columbia University Vagelos College of Physicians and Surgeons.

The findings could lead to new biomarkers for predicting the onset of these cancers and to a new class of cancer therapies that prevent or correct harmful changes in genome architecture.

The study was published online Feb. 1 in the journal Nature Genetics.

Antibodies are made by immune cells called B cells through a series of carefully controlled chromosome rearrangements and "good" mutations that allow the cell to make a wide array of different antibodies. "Although these changes are essential for generating the vast diversity of antibodies, there is a risk that 'bad' mutations will occur and lead to B cell-derived cancers," says study leader Uttiya Basu, PhD, professor of microbiology & immunology at Columbia University Vagelos College of Physicians and Surgeons.

Basu's new study shows that a protein called DIS3 is critical in maintaining genomic architecture and preventing uncontrolled chromosome rearrangements that have the potential to cause cancer.

These new studies with mice reveal that B cells become destabilized, have more detrimental chromosomal rearrangements, and are less capable of generating specific antibodies when DIS3 is missing.

DIS3 stabilizes chromosomes by preventing the buildup of noncoding RNAs (RNAs that do not code for proteins), the study also reveals.

"The massive accumulation of these RNAs perturbs the way the genome is packed in the nucleus and leaves the genome vulnerable to DNA translocations," Basu says.

Because DIS3 mutations are common in people with multiple myeloma--a type of blood cancer that stems from B cells--the study may explain why these mutations contribute to the disease.

"It's possible that multiple myeloma treatment could require therapeutic interventions that prevent RNA accumulation and its effect on genome architecture," says Basu.

Future studies will focus on how genome architectural changes could be used to predict the onset of various B cell malignancies, which sometimes start out as relatively benign conditions.

The study also brings to light the role of genomic architecture maintenance for the prevention of cancer and the role of noncoding RNA in the normal production of antibodies.
-end-
More Information

The study is titled "Noncoding RNA processing by DIS3 regulates chromosomal architecture and somatic hypermutation in B cells."

The other contributors are Brice Laffleur (Columbia), Junghyun Lim (Columbia and Jeonbuk National University, South Korea), Wanwei Zhang (Columbia), Yiyun Chen (Hong Kong University of Science and Technology), Evangelos Pefanis (Columbia and Regeneron Pharmaceuticals), Jonathan Bizarro (Columbia), Carolina R. Batista (Columbia), Lijing Wu (Columbia), Aris N. Economides (Regeneron), and Jiguang Wang (Hong Kong University of Science and Technology).

The study was supported by grants from the National Insitutes of Health (RO1AI099195, RO1AI134988, and RO1AI143897), Leukemia & Lymphoma Society, Pershing Square Sohn Cancer Research Alliance, and an EMBO fellowship.

The authors declare no competing interests.

Columbia University Irving Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the Vagelos College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Irving Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cuimc.columbia.edu or columbiadoctors.org.

Columbia University Irving Medical Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.