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GENOMIC, CELLULAR AND DEVELOPMENTAL RECONSTRUCTION OFINFANT MLL-AF4+ ACUTE LYMPHOBLASTIC LEUKEMIA

GENOMIC, CELLULAR AND DEVELOPMENTAL RECONSTRUCTION OFINFANT MLL-AF4+ ACUTE LYMPHOBLASTIC LEUKEMIA

Objective

Infant cancer is very distinct to adult cancer and it is progressively seen as a developmental disease. An intriguing infant cancer is the t(4;11) acute lymphoblastic leukemia (ALL) characterized by the hallmark rearrangement MLL-AF4 (MA4), and associated with dismal prognosis. The 100% concordance in twins and its prenatal onset suggest an extremely rapid disease progression. Many key issues remain elusive:
Is MA4 leukemogenic?
Which are other relevant oncogenic drivers?
Which is the nature of the cell transformed by MA4?
Which is the leukemia-initiating cell (LIC)?
Does this ALL follow a hierarchical or stochastic cancer model?
How to explain therapy resistance and CNS involvement?
To what extent do genetics vs epigenetics contribute this ALL?

These questions remain a challenge due to: 1) the absence of prospective studies on diagnostic/remission-matched samples, 2) the lack of models which faithfully reproduce the disease and 3) a surprising genomic stability of this ALL.

I hypothesize that a Multilayer-Omics to function approach in patient blasts and early human hematopoietic stem/progenitor cells (HSPC) is required to fully scrutinize the biology underlying this life-threatening leukemia. I will perform genome-wide studies on the mutational landscape, DNA and H3K79 methylation profiles, and transcriptome on a uniquely available, large cohort of diagnostic/remission-matched samples. Omics data integration will provide unprecedented information about oncogenic drivers which must be analyzed in ground-breaking functional assays using patient blasts and early HSPCs carrying a CRISPR/Cas9-mediated locus/allele-specific t(4;11). Serial xenografts combined with exome-seq in paired diagnostic samples and xenografts will identify the LIC and determine whether variegated genetics may underlie clonal functional heterogeneity. This project will provide a precise understanding and a disease model for MA4+ ALL, offering a platform for new treatment strategies.
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Host institution

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS

Address

Carrer Muntaner 383 3/2
08021 Barcelona

Spain

Activity type

Research Organisations

EU Contribution

€ 2 000 000

Beneficiaries (1)

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FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS

Spain

EU Contribution

€ 2 000 000

Project information

Grant agreement ID: 646903

Status

Ongoing project

  • Start date

    1 January 2016

  • End date

    31 December 2020

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 000 000

  • EU contribution

    € 2 000 000

Hosted by:

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS

Spain