MODELING MLL-AF4 ALL

Cell of origin/Leukemia Initiating Cell in infant Pro-B MLL-AF4+ ALL

Coordinatore	Fundació Institut de Recerca Contra la Leucemia Josep Carreras    more  Organization address address: CARRER MUNTANER 383 3/2 city: BARCELONA postcode: 8021 contact info Titolo: Mr. Nome: óscar Cognome: Fraile Sierra Email: send email Telefono: 34935572800 Fax: 34934651472
Nazionalità Coordinatore	Spain [ES]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-CIG
Funding Scheme	MC-CIG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-05-01   -   2018-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	Nome Ente NON disponibile  Organization address address: CARRER MUNTANER 383 3/2 city: BARCELONA postcode: 8021 contact info Titolo: Mr. Nome: óscar Cognome: Fraile Sierra Email: send email Telefono: 34935572800 Fax: 34934651472	ES (BARCELONA)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Infant pro-B acute lymphoblastic leukemia (ALL) carrying the fusion oncogene MLL-AF4 is associated with very brief latency and dismal prognosis. Recent studies have revealed an in utero origin of MLL-AF4 but the nature of the target cell for transformation in the embryo/fetus is unknown. Because of the mixed phenotype and the presence of MLL-AF4 in both lymphoid and myeloid lineages, hematopoietic stem/progenitor cells (HSPCs) are likely targets for transformation. The absence of bona fide disease models reflects our very poor understanding of the etiology, pathogenesis, cell of origin and secondary oncogenic events of this leukemia. Here it is proposed to create a murine model for infant MLL-AF4 pro-B ALL using lentiviral transduction of MLL-AF4 or AF4-MLL in HSPCs at different developmental stages: aorta-gonad-mesonephros (AGM), fetal liver (FL) and neonatal BM. These HSCs can be harvested from a novel BAC transgenic reporter mouse model that based on Vwf-EGFP expression divides multipotent adult HSCs, homogeneous by thus far characterized phenotypes, into two prospectively isolatable subsets: vWF HSCs (with platelet/myeloid-biased output) and vWF− HSCs (with lymphoid-biased output). Here, primary lymphoid-biased vWF− HSCs will be used to stably express the oncoproteins and then injected into lethally irradiated hosts. For the first time, we will exploit a model that deciphers HSC heterogeneity to study the transformation capacity of leukemogenic oncoproteins in a specific HSC subset.'