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Keywords
MYELOID DYSPLASIA/NEOPLASIA, SHWACHMAN SYNDROME, MONOSOMY 7, MUTATION ANALYSIS, REAL-TIME PCR, BCR/ABL REARRANGEMENT, SBDS GENE, PTPN11 GENE, RUNX1 GENE

New insights into the mutational load and into the possibilities of cytogenetic and molecular monitoring of myeloid dysplasia/neoplasia

Abstract
The purpose of this research programme is to analyse some of the gene and chromosome mutations, both constitutional and acquired, which cause myeloid dysplasia/neoplasia. The aims are both speculative, in order to identify nosological subgroups characterized by specific mutations and by peculiar pathogenetic mechanisms, and practical, to optimize the follow-up of the disease course. The methods used include chromosome analyses, fluorescent in situ hybridization (FISH) and molecular techniques: in particular an original quantitative real-time PCR (RQ-PCR) technique on genomic DNA set up by one of our Research Unit (RU) will give precise and accurate quantitative results applied to patients with specific chromosome anomalies.
The main goals regard the following points.
Shwachman Syndrome, a Mendelian disease predisposing to Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML) will be investigated as to the SBDS gene mutations to confirm the diagnosis and to search for genotype correlations with the phenotype or with acquired chromosome anomalies. In the patients with the most frequent chromosome anomalies in the bone marrow, as structural rearrangements of n. 7 or deletion of the long arms of n. 20, the follow-up of the abnormal clone will be done by the mentioned techniques and the results will be compared among them. The parental origin of the abnormal chromosome will be investigated in these patients as well.
The hereditary thrombocytopenia >>>

Principal Investigator
Francesco Pasquali Università degli Studi INSUBRIA Varese-Como
Research Objectives
The mutational load at the origin of myeloid dysplasia/neoplasia includes a large spectrum of identified gene and chromosome mutations. These are gene constitutional mutations that cause Mendelian predisposing disorders, clonal gene mutations acquired in the bone marrow, constitutional chromosome anomalies (sometimes in mosaicism), and clonal chromosome anomalies acquired in the bone marrow.
This research programme is intended to analyse some of these mutations by molecular and cytogenetic techniques, in order to identify nosological subgroups, characterized by specific mutations and by peculiar pathogenetic mechanisms, and to optimize the follow-up of the disease course. This latter goal will be pursued, in particular, with a quantitative real-time PCR (RQ-PCR) technique on genomic DNA. The U. R. n. 1 has set up this original technique which is able to quantify precisely and accurately the amount of cells with a given chromosome anomaly.
The main goals are summarized in the following points.
1. Shwachman Syndrome (SS), a Mendelian disease predisposing to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), will be investigated as to the different mutations of the SBDS gene, to confirm the diagnosis, and to identify single mutations correlated to clinical features or to specific acquired chromosome anomalies. In the SS patients with the most frequent acquired chromosome changes in the bone marrow (a long-arm isochromosome 7, or a structural >>>

Timescale
24 months
National and international background
The present research programme concerns:
- Mutational analysis of patients with a myelodysplastic syndrome (MDS), acquired or associated with Mendelian predisposing disorders;
- A new monitoring method of MDS, acute myeloid leukaemia (AML) and chronic myeloproliferative diseases characterized by chromosome changes.
These two types of investigations are linked by the fact that the Mendelian disorders at risk of myeloid dysplasia/neoplasia are characterized by the presence of specific chromosome anomalies, and their monitoring is of primary importance during the disease course; on the other hand, the mutation analysis is needed to obtain a diagnostic confirmation of these predisposing disorders, and may also identify subtypes of MDS/AML in which specific chromosome anomalies may be significantly acquired.
1. MDS
MDS are usually sporadic, but rare families are known with MDS occurring in sibs, and monogenic disorders as well in which the patients have an increased risk of developing MDS. These will be discussed more precisely at the following point, but include, for instance, Shwachman Syndrome (SS), Fanconi Anaemia (FA), Kostman Disease (KD), Cyclic Neutropenia (CN). These observations indicate that mutations in several different genes may cause or contribute to the development of the MDS phenotype.
The definition of different MDS subtypes related to specific mutations of identified genes may lead to a better classification, and will >>>