A team led by researchers at University of Texas MD Anderson Cancer Center recently revealed new insights on the link between dysfunctions in telomeres and myelodysplastic syndromes (MDS). The study was published in the journal Cancer Cell and is entitled “Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome.”
MDS refers to a group of blood cell disorders in which the bone marrow is unable to produce mature healthy blood cells. It mainly affects elderly individuals (60 years and older) and is characterized by low levels of red blood cells (anemia), white blood cells (neutropenia) or platelets (thrombocytopenia). The blood cells produced in MDS are dysfunctional due to dysplasia, an abnormal cell shape or morphology. Patients with MDS may also experience spontaneous bleeding, easy bruising, shortness of breath, fatigue and infections.
The risk of developing MDS is known to be associated with an advanced age, family history, gender (more common in men), smoking, therapy-induced DNA damage (like chemotherapy or radiation therapy) and/or shorter telomeres. Telomeres correspond to the caps at the end of the DNA strand that protect the edge of the chromosomes from degradation and from fusion with other chromosomes.
“MDS risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS is unknown,” said one of the study’s lead authors Dr. Simona Colla in a news release.
Researchers have now discovered a direct connection between telomere degeneration and MDS development. The team has analyzed mouse and human cells and found that the DNA damage caused by dysfunctional telomeres repressed the expression of a gene called SRSF2. This gene is an RNA splicing gene, meaning that it plays a role in the maturation of RNA molecules, and is involved in several cellular processes. In turn, inhibition of SRSF2 expression affects the ability of specific blood cells called common myeloid progenitors (CMPs) to differentiate or fully mature resulting in the development of MDS.
“Our study provided genetic evidence that DNA damage caused by telomere loss is linked to this disorder,” said Dr. Colla. “This study established an intimate link across telomere biology, aberrant RNA splicing and CMP differentiation,” added the study’s senior author Dr. Ron DePinho. “This may suggest that strategies to mitigate this DNA damage may be useful for preventing and/or treating MDS.”
The research team concluded that a poor MDS prognosis is strongly correlated to short telomeres and high DNA damage in CMP cells. “This improved understanding should provide highly specific risk biomarkers for preventing and treating this incurable disease,” concluded Dr. Colla.