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<
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<