Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression

摘要

Mantle cell lymphoma is an aggressive, non-curable B-cell lymphoma, characterized by the translocation t(11;14)(q13;q32) involving CCND1 and a high number of additional genetic alterations. Chromosomal gains of 7p are frequent in mantle cell lymphoma, with insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3 aka IMP3) being the most upregulated gene in this region. IGF2BP3 is a member of the IGF II mRNA-BP family, and increased IGF2BP3 expression is associated with an aggressive behavior in many malignant tumors. We here analyze selected genes related to IGF signaling in gene expression and genomic array data of 8 mantle cell lymphoma cell lines and 12 primary mantle cell lymphomas and study IGF2BP3 protein expression in 172 well-characterized primary mantle cell lymphomas by immunohistochemistry. The majority of mantle cell lymphoma cell lines and primary cases showed elevated IGF2BP3 mRNA expression and a subset also expressed the IGF1 and IGF2 receptors. On the protein level, 66 of 172 primary mantle cell lymphomas showed IGF2BP3 expression in >50% of tumor cells, and strong IGF2BP3 protein expression was highly associated with increased proliferation as measured by the Ki-67 index, but not with overall survival of mantle cell lymphoma patients. Only a subset of mantle cell lymphomas with marked IGF2BP3 expression had an underlying chromosomal gain in 7p, suggesting that additional mechanisms are involved in the upregulation of IGF2BP3 in mantle cell lymphoma. In seven paired mantle cell lymphoma samples, IGF2BP3 protein expression remained constant between primary diagnosis and relapse. Increased IGF2BP3 expression and, potentially, enhanced IGF signaling may contribute proproliferative stimuli in the evolution of mantle cell lymphoma tumor cells.