PRDM16 IN AML · Investigation of the functions of a novel protein, PRDM16, rearranged in cases of acute myeloid leukaemia with rare translocations
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-04-01 → 2007-03-31
- EU contribution
- €143,179
- Participants
- 1
- Scheme
- EIF
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
The proposed research project plans to investigate the functions of a novel protein, PRDM16 (MEL1), in leukaemogenesis. PRDM16 is a member of the SET domain family of histone lysine methyltransferases and was recently identified by the host laboratory to be rearranged in three cases of acute myeloid leukaemia carrying rare translocations.In the first case, full length PRDM16 is aberrantly expressed, whereas in the second case, a deleted PRDM16 lacking the SET domain (delPRDM16) is formed. In the third case, an AML1-PRDM16 fusion protein results. We plan to investigate how PRDM16, delPRDM16 and AML1-PRDM16 can give rise to AML. In particular we wish to investigate the importance of the SET domain, how fusion to AML1 alters the function of PRDM16, and whether AML1-PRDM16 can function in a similar way to AML1-ETO.In vitro assays will initially be performed to investigate the biological phenotypes induced by each protein (PRDM16, delPRDM16, AML1-PRDM16 or AML1-ETO). The proteins will be over-expressed in murine haematopoietic progenitor cells (lin- cells) and will be assessed for their ability to block myeloid differentiation, increase survival upon genotoxic stress, and increase self-renewal.In vivo assays will also be carried out to test the ability of the proteins to induce leukaemia in mice. In order to identify target genes commonly regulated by AML1-PRDM16 and AML1-ETO, Affymetrix gene expression microarrays will be employed. The proposed project will yield many important insights into the functions of PRDM16 and how its aberrant expression contributes to leukaemia.The researcher has a background in mapping fusion genes in cancer and will therefore greatly expand her repertoire of laboratory skills by performing functional studies on a novel protein. The project will not only allow the researcher to become a highly skilled and independent scientist, but will make an important contribution to European cancer research.
Original text from CORDIS.
Participants
- EUROPEAN INSTITUTE OF ONCOLOGY (ISTITUTO EUROPEO DI ONCOLOGIA) · MILANOCoordinatorCity levelItaly
Links
Data: CORDIS, © European Union