Aberrant packaging of chromosomes in the nuclei of B lymphocytes may 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.
New biomarkers for the early diagnosis of a variety of cancers and a new class of cancer therapies that prevent or correct harmful changes in genome architecture, may be developed based on these novel findings.
The study, “Noncoding RNA processing by DIS3 regulates chromosomal architecture and somatic hypermutation in B cells,” was published in the journal Nature Genetics.
Numerous rapid, “good” mutations including large chromosomal rearrangements occur through a series of carefully orchestrated genetic changes and result in the synthesis of an array of high-affinity antibodies in B lymphocytes that specifically bind and neutralize the multitudes of foreign elements (antigens) that enter the body. This molecular mechanism that diversifies B cell antibodies is called somatic hypermutation (SHM).
“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,” said study leader Uttiya Basu, PhD, professor of microbiology and immunology at Columbia University Vagelos College of Physicians and Surgeons.
A new study from Basu’s team shows that a protein called DIS3 is critical in maintaining genomic architecture and prevents haphazard chromosome rearrangements that can potentially cause cancer.
The gene DIS3 codes for an enzyme that chops up noncoding RNA—RNAs that do not code for proteins—and is a cog in the critical RNA surveillance machinery called the “RNA exosome complex” that keeps track of how many noncoding RNAs are permitted at any time in the cell’s cytosol, thus maintaining proper biological function in cells. An abnormal build-up of noncoding RNAs disrupts diverse biological processes.
The authors generated an experimental mouse model to study the effect of DIS3 deficiency. To generate this model, the group created a COIN or conditional-inversion allele of the Dis3 gene where a green fluorescent protein (GFP) is expressed once a Cre recombinase enzyme flips the orientation of the DIS3 gene to knock it out.
Mice with the DIS3 gene thus inactivated, have impaired DNA repair systems, B lymphocytes that become increasingly unstable, accumulate more harmful chromosomal rearrangements (chromosomal translocations), and are less capable of generating different classes of specific high-affinity antibodies.
DIS3 stabilizes chromosomes by preventing the buildup of noncoding RNAs, the study revealed. Accumulation of DNA and RNA hybrids changes the distribution of mutations in the B cell genome by preferentially exposing one of the two strands of DNA to enzymatic removal of chemical groups called amines, a process called deamination. This affects the patterns of mutation distribution during SHM and affects the variety of antibodies produced by B cells.
“The massive accumulation of these [noncoding] RNAs perturbs the way the genome is packed in the nucleus and leaves the genome vulnerable to DNA translocations,” Basu added.
Earlier studies have shown that DIS3 mutations are common in patients with multiple myeloma, a type of blood cancer that stems from abnormally dividing B cells. The current study may explain why these DIS3 mutations result in myelomas.
“It’s possible that multiple myeloma treatment could require therapeutic interventions that prevent RNA accumulation and its effect on genome architecture,” said Basu.
Exploiting genome architectural changes to develop diagnostic tools that could predict the onset of various B cell malignancies that start out as relatively benign conditions, will need further studies.
The study highlights the role of genomic architecture maintenance for the prevention of cancer, in particular, the critical role of DIS3-mediated noncoding RNA processing in the architectural organization of the B-cell genomes and the generation of mutations that diversify the antibody repertoire of immune systems.