Alterazioni del gene NPM nelle mielodisplasie con delezione 5q-

Myelodysplastic syndromes (MDS) include a heterogeneous group of disease characterized by dysplasia of one or more bone marrow cell lineages, usually with prominent ineffective erythropoiesis and genomic instability leading to anaemia and enhanced risk to transformation to secondary acute myeloid leukemia (AML) . Thus MDS is often diagnosed on the basis of chronic macrocytic anaemia accompanied or not by leukocytopenia and/or thrombocytopenia. The deletion of 5q (5q-) is a frequent clonal chromosomal abnormality in patients with MDS. MDS with 5q- as a sole chromosome alteration is characterized by isolated anaemia, elevated platelet count and a favourable prognosis when compared to other forms of MDS . When the 5q- accompanies additional chromosome defects, it leads to poor-risk karyotypes with dramatically different prognostic features . NPM1 is a versatile nuclear phosphoprotein that plays multiple roles in ribosome biogenesis and transport, cytoplasmic-nuclear trafficking, centrosome duplication and regulation of p53 . The NPM1 gene is located in chromosome 5q35 and is involved in a number of human haematopoietic malignancies, such as promyelocytic leukaemia , anaplastic large cell lymphoma , and AML. NPM1 has also been found mutated in approximately 35% of acute myeloid leukaemia cases . Furthermore the 5q region to which NPM1map is deleted in a number of MDS and loss of chromosome 5 is a frequent finding in MDS . In a recent paper, Grisendi and co-workers showed that NPM1 is essential to maintain genomic stability. They demonstrated that NPM1 is haploinsufficient for regulating centrosome duplication as NPM1 heterozygous cells show aberrant centrosome numbers, genomic instability and aneuploidy. We analyzed the presence of NPM1 gene deletion, methylation and mutations in 45 patients affected by MDS and in 5 patients with AML secondary to MDS carrying the 5q- abnormality as sole chromosomal alteration or associated with additional chromosome defects. Group 1 (17 patients) consisted of patients who present the 5q deletion as sole anomaly as determined by cytogenetics: 10 AR (59%), 1 ARS (6%), 1 AREB (6%), 4 AREB-T (23%) and 1 AML (6%). Group 2 ( 33 patients) consisted of patients who present the 5q deletion associated with additional chromosome defects: 5 AR (15%), 1 ARS (3%), 10 AREB (24%), 13 AREB-T (46%) e 4 AML (12%) The CpG island of the NPM1 gene was unmethylated in all the samples analyzed including patients with isolated 5q- and with complex karyotype. The mutational status of NPM1 exon 12 showed wild type NPM1 in all patient. The FISH analysis of the NPM1 locus revealed deletion of one copy of the gene in 7 cases. Interestingly all the cases with NPM1 deletion are always associated with complex karyotypes and a high-risk disease. May be considered that the aploinsufficienza of the NPM1 gene is not sufficient alone to determine the occurrence of a complex karyotype but may contribute with other genetic mechanisms for its establishment. With the test of Fisher, has shown a trend of association between the deletion of NPM1 and complex karyotype (p = 0.08); most likely by increasing the number of cases analyzed could be obtained a statistical significance.