Increased expression of Ki-67 in mantle cell lymphoma is associated with de-regulation of several cell cycle regulatory components, as identified by global gene expression analysis

Abstract

BACKGROUND AND OBJECTIVES: Mantle cell lymphoma (MCL) is an aggressive disease. Patients with this malignancy have a median survival of 3 years. To better understand disease progression, which is characterized by increased proliferation, we analyzed the gene expression of MCL with different proliferative indices, as determined by immunohistochemical staining for Ki-67. Furthermore, primary and relapsed tumors were compared to identify the possible growth advantages possessed by cells which persist after therapy and which might evolve into a tumor relapse. DESIGN AND METHODS: Twenty-one samples of MCL were analyzed, using the Affymetrix U95Av2 chip, containing probes for approximately 12,000 transcripts. Samples with a high versus low fraction of Ki-67+ cells were compared as were relapsed versus primary tumors. Immunohistochemistry was used to confirm the expression of some gene products. RESULTS: A distinct genetic signature, consisting of 32 genes, was found when comparing Ki-67high with Ki-67low MCL. The signature consisted of genes involved in cellular processes, such as mitotic spindle formation, gene transcription and cell cycle regulation, e.g. components of the p53 and retinoblastoma protein (pRb) pathways. Of note, cyclin D1, the hallmark of MCL, as well as Ki-67 were up-regulated in the samples with a high proliferative index. Comparing primary vs. relapsed tumors, 26 individual genes were found, several involved in cell adhesion. Furthermore, increased expression of transferrin receptor was found in the relapsed tumors. INTERPRETATION AND CONCLUSIONS: A genetic signature distinguishing Ki-67high MCL from Ki-67low was established. The generated signature was used to assign new MCL samples to the high proliferative group, validating the association between these genes and proliferation in MCL.