Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature. Consistent with this, we identified that VS MM exhibit reduced heme biosynthesis and curiously elevated hemin (oxidized heme) uptake. Supplementation with hemin or protoporphyrin IX (heme lacking iron) promotes Ven resistance while targeting ferrochetalase, the penultimate enzyme involved in heme biosynthesis, increases Ven sensitivity in cell lines and primary MM cells. Mechanistically, heme-mediated activation of pro-survival RAS-RAF-MEK signaling and metabolic rewiring, increasing de novo purine synthesis, were found to contribute to heme-induced Ven resistance. Co-targeting BCL-2 and MCL-1 suppresses heme-induced Ven resistance. Interrogation of the MMRF CoMMpass study of patients shows increased purine and pyrimidine biosynthesis to corelate with poor progression free survival and overall survival. Elevated heme and purine biosynthesis gene signatures were also observed in matched relapse refractory MM, underscoring the relevance of heme metabolism in therapy refractory MM. Overall, our findings reveal for the first time a role for extrinsic heme, a physiologically relevant metabolite, in modulating proximity to the apoptotic threshold with translational implications for BCL-2 antagonism in MM therapy.