This novel discovery is expected to improve care and allow for better targeted treatments for patients who are at high risk of these chromosomal abnormalities.
Also known as Kahler’s disease, multiple myeloma (MM) is a type of bone marrow cancer characterised by the abnormal expression of malignant plasma cells. Normally, healthy plasma cells help combat infections by producing antibodies that recognise and attack germs. However, when plasma cells become cancerous, they can accumulate in the bone marrow, overtake healthy blood cells, and synthesise abnormal antibodies that can lead to serious complications. Despite the advancements in MM therapeutics over the years, the treatment outcome for patients possessing two or more high-risk prognostic events remains poor.
Hoping to address this unmet clinical need, a group of researchers led by Professor Chng Wee Joo from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) embarked on a study to uncover how exactly certain chromosomal abnormalities contribute to poor outcomes in MM patients.
The deletion of chromosome 17p13 (17p13(del)) and the gain of chromosome 1q21 (1q21(gain)) have long been established as high-risk biomarkers of MM. However, there has been limited research to determine how the presence of both chromosomal abnormalities influences the outcomes in MM patients. In their study, Prof. Chng and colleagues discovered that MM cells of patients that harbour concomitant 17p13(del) with 1q21(gain) have loss of functional p53 and NEIL1 respectively, both of which are important DNA repair genes. In addition, MM cells of this high-risk patient group exhibited defective DNA damage response that is linked to high genomic instability and persistent activation of the Chk1 pathway, the latter of which regulate the cell cycle.
Interestingly, the scientists also found that when NEIL1, an enzyme that cleaves DNA bases damaged by reactive oxygen species, and p53, a well-known tumour suppressor protein that induces the cell cycle arrest, are inactivated, cells become highly dependent on the Chk1 pathway. This suggests a synthetic lethal relationship between abnormalities in Chk1, NEIL1, and p53.
As one of the first proof-of-concept studies focusing on this high-risk myeloma patient subgroup, their results have successfully demonstrated the biological and therapeutic potential of Chk1 inhibition to target DNA damage response and genomic instability presented by high-risk patients with co-occurrence of the two chromosomal abnormalities. By discovering the Achilles’ heel of MM, they have paved the way to develop more effective treatment options.
Going forward, Prof. Chng and his team intend to establish Chk1 inhibitors as the standard of care and targeted treatment for 17p13(del)-1q21(gain) high-risk patients. In particular, they plan to further study the leverage of this genomic instability on the various novel therapies for MM, including immune-based and cell therapy products.
Source: Teoh et al. (2022). p53-NEIL1 co-abnormalities induce genomic instability and promote synthetic lethality with Chk1 inhibition in multiple myeloma having concomitant 17p13(del) and 1q21(gain). Oncogene, 41, 2106–2121.