Integration between MCL1 gene co-expression module and the Revised International Staging System enables precise prognostication and prediction of response to proteasome inhibitor-based therapy in individual multiple myeloma
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ABSTRACT: We recently identified a gene module of 87 genes co-expressed with MCL1 (MCL1-M), a critical regulator of plasma cell survival. MCL1-M captures both MM cell-intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment. MM can be clustered into MCL1-M high and MCL1-M low subtypes. While the MCL1-M high MMs are enriched in a preplasmablast signature, the MCL1-M low MMs are enriched in B cell-specific genes. In multiple independent datasets, MCL1-M high MMs exhibited poorer prognosis compared to MCL1-M low MMs. Re-analysis of the phase III HOVON-65/GMMG-HD4 showed that only MCL1-M MMs, but not MCL1-M low MMs, benefited from bortezomib-based treatment. To translate the MCL1-M clustering scheme into a platform for individual diagnosis, we refined the classifier genes and developed a support vector machine-based algorithm. Individual MMs with transcriptome assessed at the RNA-seq or U133 plus 2.0 array platform can be robustly assigned as the MCL1-M high or low subtype with high confidence. Analyses of the MM samples in the HOVON-65/GMMG-HD4 trial and APEX trial reinforce that only MCL1-M high MMs benefit from bortezomib-based treatment with a hazard ratio of 0.58 (P = 0.010) and 0.47 (P = 0.009), respectively. Thus, MCL1-M based subtyping assigns MMs into prognostic and predictive molecular subtypes driven by subtype-specific pathogenic pathways.
ORGANISM(S): Homo sapiens
PROVIDER: GSE190042 | GEO | 2024/12/01
REPOSITORIES: GEO
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