Differential dependencies and therapeutic potential of HK2 and PKM in the hypoxic microenvironment of multiple myeloma
Multiple myeloma (MM) is a hematological malignancy that proliferates within the bone marrow, where hypoxic stress in the microenvironment leads to treatment resistance. In this study, we comprehensively evaluated whether hypoxia-inducible glycolytic genes represent promising therapeutic targets for MM, using in vitro functional analyses and large-scale in silico data analyses. Among the glycolytic genes whose expression is upregulated under hypoxic conditions, knockdown of HK2 and PKM strongly induced hypoxia-specific apoptosis in MM cells. Database analysis revealed that PKM is a universal survival factor across a wide range of cancer types. In contrast, HK2 exhibited extremely high disease-specific dependency, and MM showed the highest HK2 dependence among the 28 cancer types evaluated. Furthermore, while PKM expression positively correlated with ARNT (hypoxia-inducible factor 1 beta) on the 1q21 chromosome and followed a normal distribution, HK2 expression showed marked heterogeneity among patients. Clinically, high expression of HK2 and PKM is associated with a significant reduction in overall survival. The present analysis reflects total PKM expression, and the dominant role of PKM2 requires further validation. In conclusion, HK2 and PKM are poor prognostic factors for MM survival under hypoxic conditions, suggesting the importance of stratifying patients for metabolically targeted therapy based on their molecular profiles, such as HK2 expression levels and 1q21 amplification status.
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