Nair Remya, Vu An H, Freer Abigail K, Bhatia Karanpreet S, Wang Dongxue, Savani Milan R, Matulis Shannon M, Lonial Sagar, Jaye David L, Boise Lawrence H, Seo Seung-Yong, Corson Timothy W, Nooka Ajay K, Bhatt Shruti, McBrayer Samuel K, Gupta Vikas A, Hu Xin, Barwick Benjamin G, Reddi Amit R, Shanmugam Mala
Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA.
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA.
Blood. 2025 Feb 13;145(7):732-747. doi: 10.1182/blood.2024025690.
We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the B-cell lymphoma 2 (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 cyclin D1 group 2 subgroup of MM from the Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (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 exhibits reduced heme biosynthesis and curiously elevated hemin (oxidized heme) uptake. Supplementation with hemin or protoporphyrin IX (heme lacking iron) promotes Ven resistance, whereas targeting ferrochetalase, the penultimate enzyme involved in heme biosynthesis, increases Ven sensitivity in cell lines and primary MM cells. Mechanistically, heme-mediated activation of prosurvival rapidly accelerated fibrosarcoma-rat sarcoma virus-mitogen-activated protein kinase (MEK) signaling and metabolic rewiring, increasing de novo purine synthesis, were found to contribute to heme-induced Ven resistance. Cotargeting BCL-2 and myeloid cell leukemia-1 suppresses heme-induced Ven resistance. Interrogation of the Multiple Myeloma Research Foundation 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.
我们之前证明，在多发性骨髓瘤（MM）中，内在电子传递链（ETC）活性降低可预测并促进对B细胞淋巴瘤2（BCL-2）拮抗剂维奈克拉（Ven）的敏感性。血红素是一种含铁的辅基和代谢物，对维持ETC活性至关重要。对来自骨髓瘤与个人基因谱评估相关临床结果（CoMMpass）试验（NCT01454297）的MM细胞周期蛋白D1第2亚组进行分析，该亚组可作为维奈克拉敏感MM（VS MM）的替代指标，结果显示保守的血红素生物合成途径基因特征的表达降低。与此一致的是，我们发现VS MM的血红素生物合成减少，且奇怪的是血红素（氧化型血红素）摄取增加。补充血红素或原卟啉IX（不含铁的血红素）会促进维奈克拉耐药，而靶向血红素生物合成中倒数第二个酶亚铁螯合酶，可增加细胞系和原代MM细胞对维奈克拉的敏感性。从机制上讲，血红素介导的促生存快速加速纤维肉瘤-大鼠肉瘤病毒-丝裂原活化蛋白激酶（MEK）信号传导和代谢重塑，增加嘌呤从头合成，被发现是血红素诱导维奈克拉耐药的原因。同时靶向BCL-2和髓系细胞白血病-1可抑制血红素诱导的维奈克拉耐药。对MM患者的多发性骨髓瘤研究基金会CoMMpass研究进行分析显示，嘌呤和嘧啶生物合成增加与无进展生存期和总生存期较差相关。在匹配的复发难治性MM中也观察到血红素和嘌呤生物合成基因特征升高，强调了血红素代谢在治疗难治性MM中的相关性。总体而言，我们的研究结果首次揭示了外源性血红素（一种生理相关代谢物）在调节接近凋亡阈值方面的作用，对MM治疗中BCL-2拮抗作用具有转化意义。
