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FP6

PRDM16 IN AML Informe resumido

Project ID: 8999
Financiado con arreglo a: FP6-MOBILITY
País: Italy

Final Activity Report Summary - PRDM16 IN AML (Investigation of the functions of a novel protein, PRDM16, rearranged in cases of acute myeloid leukaemia with rare translocations)

Acute myeloid leukaemia (AML) is a disease that originates in haematopoietic stem and progenitor cells. AML is often initiated by expression of the abnormal products of chromosomal translocations, but requires cooperating mutations to induce overt leukaemia.

We identified aberrant overexpression of the PRDM16 gene in five cases of leukaemia with rearrangements of 1p36, as well as in a significant subset of AML with normal karyotype. Mutations of TP53 and nucleophosmin (NPM), a regulator of p53, were associated with PRDM16 overexpression, suggesting that disruption of the p53 tumour suppressor pathway might be a cooperating event in leukaemogenesis. Two protein isoforms could be expressed from the PRDM16 gene, namely PRDM16 and sPRDM16, which differed in the presence and absence of the PR domain.

In order to understand which isoform gave rise to leukaemia, we studied their biological functions via in vitro and in vivo assays. Overexpression of the short isoform, sPRDM16, in murine bone marrow was able to induce AML with full penetrance, but only in the absence of p53. The murine leukaemias were characterised by multilineage dysplasia and dysmegakaryocytopoiesis, which were common features of human AMLs with 1p36 translocations or NPM mutations. In vitro, sPRDM16 overexpression blocked myeloid differentiation, expanded the stem cell pool and, along with loss of p53, induced immortalisation of progenitor cells. In contrast, the long isoform, PRDM16, did not demonstrate oncogenic properties. Therefore, overexpression of sPRDM16 induced abnormal stem cell growth and cooperated with disruption of the p53 pathway in the induction of myeloid leukaemia.

Contacto

Pier Giuseppe PELICCI
Tel.: +39-0257489838
Fax: +39-0257489851
Correo electrónico
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