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

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.

Field of science

  • /medical and health sciences/clinical medicine/oncology/leukemia

Call for proposal

FP7-PEOPLE-2013-CIG
See other projects for this call

Funding Scheme

MC-CIG - Support for training and career development of researcher (CIG)
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Coordinator

FUNDACION PARA LA INVESTIGACION DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA
Address
Av Fernando Abril Martorell 106
46026 Valencia
Spain
Activity type
Research Organisations
EU contribution
€ 37 500
Administrative Contact
Ana Blanco Sanchez (Dr.)

Participants (1)

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS

Participation ended

Spain
EU contribution
€ 62 500
Address
Carrer Muntaner 383 3/2
08021 Barcelona
Activity type
Research Organisations
Administrative Contact
óscar Fraile Sierra (Mr.)