Innovating Works

INFANTLEUKEMIA

Financiado
GENOMIC CELLULAR AND DEVELOPMENTAL RECONSTRUCTION OF INFANT MLL AF4 ACUTE LYMP...
GENOMIC CELLULAR AND DEVELOPMENTAL RECONSTRUCTION OF INFANT MLL AF4 ACUTE LYMPHOBLASTIC LEUKEMIA 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-... 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. ver más
30/06/2021
FUNDACIO INSTITUT...
2M€
Perfil tecnológico estimado
Duración del proyecto: 66 meses Fecha Inicio: 2015-12-02
Fecha Fin: 2021-06-30

Línea de financiación: concedida

El organismo H2020 notifico la concesión del proyecto el día 2021-06-30
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-CoG-2014: ERC Consolidator Grant
Cerrada hace 10 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
Líder del proyecto
FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEM... Actividades de investigación asociacion
Perfil tecnológico TRL 4-5 50K