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Contenu archivé le 2024-06-18

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

Objectif

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.

Appel à propositions

FP7-PEOPLE-2013-CIG
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Coordinateur

FUNDACION PARA LA INVESTIGACION DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA
Contribution de l’UE
€ 37 500,00
Adresse
AV FERNANDO ABRIL MARTORELL 106
46026 Valencia
Espagne

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Région
Este Comunitat Valenciana Valencia/València
Type d’activité
Research Organisations
Contact administratif
Ana Blanco Sanchez (Dr.)
Liens
Coût total
Aucune donnée

Participants (1)