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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 <jats:italic>MCL1<\/jats:italic> (MCL1\u2010M), a regulator of plasma cell survival. The classification system enabled prediction of the prognosis and the response to bortezomib\u2010based 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\u2010M members including MCL1, was found in about 80% of the MM with upregulated MCL1\u2010M expression. Clonal analysis showed that 1q gain tended to occur as an early clonal event. Members of MCL1\u2010M captured both MM cell\u2010intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment. MCL1\u2010M members were co\u2010expressed in mouse germinal center B cells. Together, these findings indicate that MCL1\u2010M may play previously inadequately recognized, initiating role in the pathogenesis of MM. Our findings suggest that MCL1\u2010M signature\u2010based molecular clustering of MM constitutes a solid framework toward understanding the etiology of this disease and establishing personalized care.<\/jats:p><jats:p><jats:bold>Article Summary:<\/jats:bold> A pathogenic mechanism\u2010guided 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.<\/jats:p>","DOI":"10.1002\/gcc.2","type":"journal-article","created":{"date-parts":[[2018,4,26]],"date-time":"2018-04-26T08:31:50Z","timestamp":1524731510000},"page":"420-429","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["MCL1 gene co\u2010expression module stratifies multiple myeloma and predicts response to proteasome inhibitor\u2010based therapy"],"prefix":"10.1002","volume":"57","author":[{"given":"Ayaz Ali","family":"Samo","sequence":"first","affiliation":[{"name":"School of Life Sciences, Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University Beijing 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