Schematic image, showing the R-loop resolution by REXO5 (left) and the inhibition of R-loop resolution by REXO5 mutation (right). Credit: Leukemia (2024). DOI: 10.1038/s41375-024-02362-z

A key gene that could enhance the treatment success rates of chronic myeloid leukemia (CML) has been discovered by researchers.

Professor Hongtae Kim and his research team in the Department of Biological Sciences at UNIST, in collaboration with Professor Dong-Wook Kim from Eulji University and Professor Jae Jin Kim from Hallym University, have unveiled a novel role for REXO5 (RNA Exonuclease 5) in the DNA damage response (DDR).

Their findings, published in Leukemia, suggest that REXO5 is linked to leukemia development through its role in increasing genomic instability.

CML arises from the rapid proliferation of abnormal blood cells driven by the BCR::ABL1 fusion gene, which encourages hematopoietic stem cells to produce blood cells uncontrollably. While targeted treatments like imatinib (Gleevec) have improved patient survival rates and offered potential cures, some patients face life-threatening challenges, including drug resistance or progression to the acute phase of the disease.

In their research, the team identified elevated levels of REXO5 expression in samples from 60 patients with CML, marking the first time the connection between REXO5 and the DNA damage response in leukemia has been established. Although REXO5 is known for its role in RNA processing, its involvement in CML progression was previously unrecognized.

The REXO5 protein has been shown to contribute to increased genomic instability through the formation of R-loop structures, where RNA attaches to damaged DNA. Insufficient levels of REXO5 lead to reduced DNA replication during the S-phase of the cell cycle, significantly impeding cell growth.

Moreover, REXO5 plays a crucial role in repairing damaged DNA by utilizing its RNA binding sites to interact with R-loop RNA strands and subsequently degrade them.

Professor Hongtae Kim stated, “We have unveiled the key molecular mechanisms by which REXO5 contributes to blood cancer. This achievement lays the groundwork for developing a leukemia treatment strategy focused on the DNA damage response.”

Professor Dong-Wook Kim said, “We have highlighted the potential for slowing or inhibiting the acute progression of CML through new therapeutic approaches that regulate the REXO5 protein.”