In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse.

在多发性骨髓瘤中，炎症和抗病毒途径促进疾病进展和癌症干细胞生成。使用不同的临床前模型，我们研究了干扰素调节因子 4 (IRF4) 在骨髓瘤祖细胞再生中的作用。在一个重现人骨髓瘤中 IRF4 通路激活的患者衍生异种移植模型中，我们测试了 IRF4 反义寡核苷酸 (ASO) 的作用，并确定了临床开发的先导药物 (ION251)。IRF4 过表达会扩大骨髓瘤祖细胞，而 IRF4 ASO 会损害骨髓瘤细胞存活并降低 IRF4 和 c-MYC 表达。IRF4 ASO 单一疗法可阻止异种移植模型中的肿瘤形成和骨髓瘤传播，从而提高动物存活率。而且，IRF4 ASO 根除骨髓瘤祖细胞和恶性浆细胞，同时保留正常的人类造血干细胞发育。从机制上讲，IRF4 抑制会破坏细胞周期进程，下调干细胞和细胞粘附转录物表达，并提高对骨髓瘤药物的敏感性。这些发现将使选择性 IRF4 抑制剂的快速临床开发成为可能，以防止骨髓瘤祖细胞驱动的复发。