The role of microRNA in multiple myeloma: biological and clinical implications
Multiple myeloma (MM) is characterized by the malignant proliferation of bone marrow plasma cells. It may develop from a premalignant age-progressive condition called monoclonal gammopathy of undetermined significance but its pathogenesis remains largely unknown. Despite high-dose chemotherapy with stem cell support and the introduction of novel agents such as thalidomide and the proteasome inhibitor bortezomib, MM remains a largely incurable disease. Over the last years, non-random genetic lesions have been identified in MM and these have been related to clinical course and response to therapy. MMs can be divided into two approximately equivalent groups, hyperdiploid (HD) and non-hyperdiploid (NHD) tumors. HD MM are associated with trisomies of odd chromosomes and a low prevalence of chromosomal translocations involving the immunoglobulin heavy chain locus (IGH) on chromosome 14q32. NHD tumors are frequently associated with the constitutive activation of CCND1(11q13), CCND3(6p21), MAF(16q23), MAFB(20q11), or FGFR3/MMSET(4p16.3) genes as a result of IGH translocations. The mechanisms underlying such dichotomy have not been elucidated but it has been documented that HD patients have a generally better prognosis.
Genomic data generated by high-throughput technologies in the last decade, particularly by gene expression profiling (GEP) analysis, have contributed further to demonstrate the remarkable genetic diversity of MM. It has been demonstrated that distinct genetic lesions are associated with specific transcriptional patterns. Furthermore, molecular classifications which take into account genomic signatures such as proliferation-related genes or Cyclin D expression, IGH translocations or hyperdiploidy have been proposed. The final goal is to better elucidate the relationship between clinical outcome and the biological features of MM patients to eventually personalize treatment. However, all these advances are still not sufficient to explain the genesis and evolution of the disease; yet, the identification of GEP profiles may be only partially informative of complex regulatory networks in the disease.
The discovery of different classes of small non-coding RNAs including microRNAs (miRNAs) and more recently those called ultraconserved regions (UCRs), has added a further level of complexity to normal and cancer cell biology. In fact, miRNAs exert important regulatory roles in cell cycle, survival and differentiation programs at both transcriptional and post-transcriptional levels. It has been reported that the combination of non-random chromosomal abnormalities and other types of genetic alterations or epigenetic events may contribute to the deregulation of miRNA in many types of tumors including hematologic disorders. In addition, UCRs may be regulated by miRNAs and may have aberrant signatures in human leukemias and carcinomas with functional consequences in tumor biology. However, despite very recent contributions from our and other groups, the available information on miRNA involvement in MM is limited.
The aim of the proposal is to extend our investigation of the role of miRNAs in myelomagenesis. We plan to inspect both the clinical relevance of miRNAs by profiling cohorts of MM patients in different clinical phases or MM patients included in specific clinical trials, and biological roles by in vitro model systems. In addition, the role of UCRs in MM and their relationship with mRNA and miRNA expression will be evaluated.
- Principal Investigators:
- Financing institution:
- FONDAZIONE AIRC PER LA RICERCA SUL CANCRO ETS
- ASS_NAZ - Bandi da Associazioni e altri Finanziatori privati nazionali
- Project leader:
- UNIVERSITA' DEGLI STUDI DI MILANO