RICERCA ITALIANA     

Myelodysplastic syndromes: pathogenetic models and promise of new therapies

Università Cattolica del Sacro Cuore

Abstract

BACKGROUND
Myelodysplastic syndrome (MDS) are a heterogeneous group of clonal haematopoietic disorders, which exhibit ineffective haematopoiesis leading to pancytopenia and with an increased risk (30%) of transformation to acute myeloid leukaemia (AML). Expansion of the abnormal clone is characterized by morphological dysplasia, impaired differentiation, defective cellular functions, and genetic instability. Clonal cytogenetic abnormalities are demonstrable in 40%-50% of patients with primary MDS and in up to 80% of patients with secondary or treatment-induced MDS. The specific chromosome affected and the number of chromosomal abnormalities (i.e., complexity) offer powerful prognostic information. Evolution to AML, however, may be influenced by epigenetic events. For example, silencing of the proto-oncogene p15INK4b by methylation is detected in >70% of patients experiencing AML evolution.
Preclinical investigations indicate that reciprocal interactions between the malignant clone and the microenvironment serve to create a hostile milieu that reinforces ineffective blood cell production. Ineffective hematopoiesis, the hallmark of MDS, arises from impaired progenitor responsiveness to normal trophic signals and excess local generation of inhibitory cytokines, which promote accelerated apoptosis of progenitors and their progeny. Evidence supporting this model derives from cytokine neutralization studies and the direct relationship between plasma tumor necrosis >>>

Principal Investigator

Giuseppe LEONE Università Cattolica del Sacro Cuore

Research Objectives

Aim of the project is to identify specific biological profiles of MDS patients, classified according to WHO criteria, at diagnosis and after treatment with drugs able to revert epigenetic changes. MDS subtypes will be identified and characterized by performing genetic and epigenetic studies, which will be correlated to immunophenotype and morphology.

a) TASKS OF GENETIC STUDIES
1) BIOLOGICAL DEFINITION OF MYELODYSPLASTIC SYNDROMES WITH MISSING GENETIC LABELS IN THE WHO CLASSIFICATION.
This part of the project has been conceived to discover new cytogenetic/molecular markers to define new entities within the WHO classification and to identify new and/or cryptic genomic lesions either in cases with karyotypic anomalies or in normal and failed cases at conventional cytogenetics.

2) IDENTIFICATION OF NEW GENES AND MOLECULAR MECHANISMS UNDERLYING MYELODYSPLASTIC SYNDROMES AND OTHER RELATED MYELOID NEOPLASMS.
Comparative Genomic Hybridization (CGH) and metaphase FISH in MDS with complex karyotype will be performed. Molecular investigations will include the characterization of genes DUP16 (a new oncosuppressor gene at 12p13, encoding for a MAPK phosphatase)and BUP98.

3)MATRIX-CGH AND GENE EXPRESSION ANALYSIS ON CHROMOSOMES AND ON MICROARRAYS. Matrix-CGH is helpful to increase the resolution power of CGH in metaphase.

4)CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF MDS WITH INVOLVEMENT OF 3q21 AND 3q26 >>>

Timescale

24 months

National and international background

Myelodysplastic syndromes(MDS) are a heterogeneous group of clonal haematopoietic disorders, which exhibit ineffective haematopoiesis leading to pancytopenia and with an increased risk (30%) of transformation into acute myeloid leukaemia (AML). Expansion of the abnormal clone is characterized by morphological dysplasia, impaired differentiation, defective cellular functions, and genetic instability. Clonal cytogenetic abnormalities are demonstrable in 40%-50% of patients with primary MDS and in up to 80% of patients with secondary or treatment-induced MDS. The specific chromosome affected and the number of chromosomal abnormalities (i.e., complexity) offer powerful prognostic information. Results from cytogenetic studies applied to hematological malignancies provided new insights for new classifications. First, the so-called MIC (Morphology, Immunology, Cytogenetics) classification of acute and chronic leukaemias, as well as of MDS, was based on specific associations between morphological, immunological and cytogenetic features. More recently, the World Health Organisation (WHO) proposed a wide ranging classification of hematological malignancies and established the state of the art in genetic diagnosis of lympho- and myelo-proliferative diseases. Cytogenetics and molecular biology of several diseases are well known, however the most still remain unknown.
Among acute myeloid leukemias and myelodysplastic syndromes around 60% of cases with both normal karyotype or >>>