A ground-breaking study by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has revealed crucial insights into the role of the histone methyltransferase NSD2 and its epigenetic target PKCα in causing t(4;14) translocated multiple myeloma (MM)—a high-risk subtype of blood cancer—to be more aggressive and resistant to treatment.
The study was led by Wee Joo Chng, MBBS, PhD, professor and senior principal investigator, CSI Singapore, and Phyllis Shu Yun Chong, PhD, senior research fellow, CSI Singapore. The research team discovered that NSD2 triggers elevated glycolysis through the activation of PKCα. This produces excessive lactate that fuels malignancy and undermines response to immunomodulatory drugs. The findings present potential targets to improve the treatment of MM.
Targets for therapeutic intervention
Myeloma is the second most common blood cancer: t(4;14) myeloma comprises 15–20 percent of MM cases. Compared to other types of myeloma, patients with t(4;14) myeloma have a poorer prognosis with shorter overall survival. Unfortunately, the key deregulated gene in t(4;14) myeloma is not targetable with drugs. “Our study aims to overcome the limitations of targeting the key deregulated gene in t(4;14) myeloma. It sheds light on the metabolic reprogramming of MM in response to the oxygen- and nutrient-deprived bone marrow microenvironment. By exploring the epigenome and metabolome of NSD2, we sought alternative vulnerabilities that could revolutionize treatment strategies,” said Chng, the study’s corresponding author.
The unique connection between NSD2 and cellular metabolism, mediated by histone methylation, offers new horizons in the battle against high-risk MM subtypes. The study’s impact is multifaceted, potentially influencing the development of novel medicines and noninvasive diagnostic tests.
For patients with t(4;14) myeloma, targeted metabolic interventions could bring promising therapeutic options, whether through dietary modifications or tailored pharmacological approaches. Furthermore, the discovery that lactate levels could serve as predictive biomarkers for drug response highlights the transformative potential of metabolite signatures in personalized medicine.
Toward tailored interventions and personalized care
This study, published in Cancer Research, marks a significant stride in unraveling the complexities of MM and holds promise for improving treatment outcomes for patients with high-risk subtypes.
Looking ahead, Chng and his team plan to leverage the knowledge gained from this study to design therapeutic interventions for t(4;14) myeloma. The success of their metabolic characterization of t(4;14) myeloma also paves the way for the team to extend their metabolomic framework to profile other genetically high-risk MM subtypes such as t(14;16) or with 1q21 amplifications, presenting a path towards tailored interventions and personalized care.
- This press release was originally published on the National University of Singapore website