Cel
Objectives:
? To demonstrate the in vitro and in vivo leukemogenic activity of PML/RAR, PLZF/RAR and NPM/RAR and their role in the sensitivity of the leukemic blasts to retinoic acid.
? To understand the molecular mechanisms responsible of the block of differentiation and the retinoic acid-differentiative response of the promyelocytic leukemia blasts.
Brief description:
The key objective of this research is to elucidate the molecular pathogenesis of Acute Promyelocyti Leukemia (APL) and the molecular basis of its sensitivity to the differentiative action of retinoic acid (RA). Fusion proteins involving the same portion of the retinoic acid receptor (RAR) and the PML, PLZF or NPM nuclear proteins are the genetic markers of APL. RAR mutations, however, are not sufficient to trigger the leukemic phenotype, indicating that the RAR fusion partners are instrumental in the oncogenic process. The function and biochemical activities of PML, NPM and PLZF and the mechanisms of action of the PML/, PLZF/ and NPM/RAR are unknown. While phenotypically indistinguishable, APLs with the PML/RAR or the PLZF/RAR fusion proteins differ in their sensitivity to RA differentiation: PML/RAR blasts are sensitive to RA and patients enter disease remission after RA treatment, while those with PLZF/RAR do not. The association of three different RAR fusion proteins with APL pathogenesis offers a unique opportunity for a comparative analysis of their biological and biochemical properties which shall provide information essential for understanding the mechanisms at the basis of the differentiation block in APL blasts, as well as their response to RA.
The specific objectives of this project are:
I) the generation of animal model systems of APL;
II) the definition of the biological activities of the APL-associated translocation products in cultured hematopoietic precursors;
III) the definition of the mechanisms of action of PML/RAR (transcriptional properties; structure/function relationships) and analysis of its interference with endogenous PML and RAR;
IV) the identification of the PML/RAR targets (PML/RAR regulated genes; PML-associated proteins);
V) the definition of the structure and function of the PML-Nuclear bodies;
VI) the definition of the cellular and molecular mechanisms of the response of APLs to RA and a new therapeutically active compounds (e.g. arsenic);
VII) the comparison of the biological and biochemical properties of the PML/RAR protein with other leukemia-associated fusion proteins: PLZF/RAR and HRX/epsl5.
Keywords:
Leukemia, differentiation, retinoic acid, PML/RAR, apoptosis, co-repressors, co-activators
Dziedzina nauki (EuroSciVoc)
Klasyfikacja projektów w serwisie CORDIS opiera się na wielojęzycznej taksonomii EuroSciVoc, obejmującej wszystkie dziedziny nauki, w oparciu o półautomatyczny proces bazujący na technikach przetwarzania języka naturalnego.
Klasyfikacja projektów w serwisie CORDIS opiera się na wielojęzycznej taksonomii EuroSciVoc, obejmującej wszystkie dziedziny nauki, w oparciu o półautomatyczny proces bazujący na technikach przetwarzania języka naturalnego.
- nauki przyrodniczenauki biologicznebiochemiabiocząsteczkibiałka
- nauki przyrodniczenauki biologicznegenetykamutacja
- medycyna i nauki o zdrowiumedycyna klinicznaonkologiabiałaczka
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CSC - Cost-sharing contractsKoordynator
20141 MILANO
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