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The t(4;14) multiple myelomas: 15 years after Volume 19, issue 2, Mars-Avril 2013

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Service d’immunohématologie clinique, EA3963, institut universitaire d’hématologie, hôpital Saint-Louis, 75010, Paris

Despite new therapeutic advances, multiple myeloma (MM) is still an uncurable disease. The heterogeneous clinical outcome of the disease is in part explained by two main underlying cytogenetic abnormalities, hyperdiploidy (40%) and 14q chromosomal translocations (60%). The t(4;14) translocation is present in 15% of MM and indicates a clinic-biological entity associated with an improved but yet significantly poor prognosis despite the use of proteasome inhibitor. The subgroup of t(4;14) is actually heterogeneous itself including smoldering MM contrasting with aggressive forms of the disease. At the molecular level, the t(4;14) leads to the dysregulation of two potential oncogenes FGFR3 and MMSET. Fifteen years after t(4;14) identification, the role of FGFR3, a tyrosine kinase receptor which is both the target of activating mutations in 5 to 10% of patients but not expressed in 25 to 30% of cases, remains unclear. FGFR3 may act in cooperation with other oncogenes and several trials using tyrosine kinase inhibitors in combination with “novel” agents are now ongoing. The recent progress come from the understanding of MMSET activity overexpressed in 100% of t(4;14) MM. MMSET is an histone methyl transferase able to dimethylate H3K36 leading to the transformation of fibroblast in vitro. Surprisingly, MMSET is also involved in the resolution of DNA double strand breaks and DNA repair, through the methylation of histone H4K20. MMSET may play a role in the tumor progression and genomic instability, frequently observed in this subgroup of MM. In addition, the expression of the different forms of MMSET, derived from the 3 different breakpoints on chromosome 4 may explain in part the prognostic heterogeneity of t(4;14) MM. These recent data may help to define novel “risk-adapted” therapeutic strategies based on the risk of genomic instability and may lead to the identification of new therapeutic target to improve the prognostic of the more serious forms of the disease.