Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies, including multiple myeloma (MM). However, this plasma cell malignancy remains incurable, and novel therapies are therefore urgently needed. Whole-genome transcriptome analyses in a large cohort of MM patients demonstrated that alterations in pre-mRNA splicing (AS) are frequent in MM. This manuscript describes approaches to identify disease-specific alterations in MM and proposes RNA-based therapeutic strategies to eradicate such alterations. As a “proof of concept”, we examined the causes of aberrant HMMR (Hyaluronan-mediated motility receptor) splicing in MM. We identified clusters of single nucleotide variations (SNVs) in the HMMR transcript where the altered splicing took place. Using bioinformatics tools, we predicted SNVs and splicing factors that potentially contribute to aberrant HMMR splicing. Based on bioinformatic analyses and validation studies, we provided the rationale for RNA-based therapeutic strategies to selectively inhibit altered HMMR splicing in MM. Since splicing is a hallmark of many cancers, strategies described herein for target identification and the design of RNA-based therapeutics that inhibit gene splicing can be applied not only to other genes in MM but also more broadly to other hematological malignancies and solid tumors as well.
新型药物的发现改变了包括多发性骨髓瘤在内的大多数血液系统恶性肿瘤的治疗模式。然而，这种浆细胞恶性肿瘤目前仍无法治愈，因此迫切需要新的治疗方法。对大规模多发性骨髓瘤患者进行的全基因组转录组分析表明，前体mRNA剪接的改变在多发性骨髓瘤中较为常见。本文阐述了识别多发性骨髓瘤中疾病特异性剪接异常的方法，并提出了基于RNA的治疗策略以消除此类异常。作为"概念验证"，我们研究了多发性骨髓瘤中HMMR（透明质酸介导的运动受体）异常剪接的原因。我们在发生剪接异常的HMMR转录本中鉴定出单核苷酸变异簇。通过生物信息学工具，我们预测了可能导致HMMR异常剪接的单核苷酸变异和剪接因子。基于生物信息学分析和验证研究，我们提出了基于RNA的治疗策略，用于选择性抑制多发性骨髓瘤中异常的HMMR剪接。由于剪接异常是多种癌症的共同特征，本文所述的靶点识别方法以及抑制基因剪接的RNA治疗策略设计，不仅适用于多发性骨髓瘤的其他基因，还可更广泛地应用于其他血液系统恶性肿瘤和实体瘤。
肿瘤(癌症)患者之家