School of Life Sciences, Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing, China.
Department of Hematology, Changzhou No. 3 People's Hospital, Changzhou, China.
Genes Chromosomes Cancer. 2018 Aug;57(8):420-429. doi: 10.1002/gcc.2.
Multiple myeloma (MM) is the second most common hematologic cancer, characterized by abnormal accumulation of plasma cells in the bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems of prognostic impact have been proposed, but they do not predict the response to treatment nor do they correlate to plasma cell development pathways. Here we describe the classification of MM into two distinct subtypes based on the expression levels of a gene module coexpressed with MCL1 (MCL1-M), a regulator of plasma cell survival. The classification system enabled prediction of the prognosis and the response to bortezomib-based therapy. Moreover, the two MM subtypes were associated with two different plasma cell differentiation pathways (enrichment of a preplasmablast signature versus aberrant expression of B cell genes). 1q gain, harboring 63 of the 87 MCL1-M members including MCL1, was found in about 80% of the MM with upregulated MCL1-M expression. Clonal analysis showed that 1q gain tended to occur as an early clonal event. Members of MCL1-M captured both MM cell-intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment. MCL1-M members were co-expressed in mouse germinal center B cells. Together, these findings indicate that MCL1-M may play previously inadequately recognized, initiating role in the pathogenesis of MM. Our findings suggest that MCL1-M signature-based molecular clustering of MM constitutes a solid framework toward understanding the etiology of this disease and establishing personalized care. Article Summary: A pathogenic mechanism-guided molecular classification would facilitate treatment decision and etiology research of multiple myeloma. On the basis of the expression levels of a gene module coexpressed with MCL1, we have established a classification scheme assigning multiple myeloma into two subtypes with distinct prognosis, treatment responses and pathogenic backgrounds.
多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤，其特征是骨髓中浆细胞异常积聚。MM 广泛的生物学和临床异质性阻碍了有效的治疗和病因研究。已经提出了几种具有预后影响的分子分类系统，但它们既不能预测对治疗的反应，也不能与浆细胞发育途径相关联。在这里，我们根据与 MCL1（调节浆细胞存活的因子）共表达的基因模块的表达水平，将 MM 分为两个不同的亚型。该分类系统能够预测预后和硼替佐米为基础的治疗反应。此外，这两种 MM 亚型与两种不同的浆细胞分化途径相关（前浆母细胞标志的富集与 B 细胞基因的异常表达）。1q 增益，含有包括 MCL1 在内的 87 个 MCL1-M 成员中的 63 个，在约 80%表达上调的 MCL1-M 的 MM 中发现。克隆分析表明，1q 增益往往作为早期克隆事件发生。MCL1-M 成员捕获了 MM 细胞内在作用的信号以及调节 MM 细胞与骨髓微环境相互作用的信号。MCL1-M 成员在小鼠生发中心 B 细胞中共同表达。这些发现表明，MCL1-M 可能在 MM 的发病机制中发挥了以前未被充分认识的起始作用。我们的研究结果表明，基于 MCL1-M 特征的 MM 分子聚类构成了理解该疾病病因和建立个体化治疗的坚实框架。文章摘要：一种基于致病机制的分子分类方法将有助于多发性骨髓瘤的治疗决策和病因研究。基于与 MCL1 共表达的基因模块的表达水平，我们建立了一种分类方案，将多发性骨髓瘤分为两种具有不同预后、治疗反应和发病机制背景的亚型。
