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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - INFANTLEUKEMIA (GENOMIC, CELLULAR AND DEVELOPMENTAL RECONSTRUCTION OFINFANT MLL-AF4+ ACUTE LYMPHOBLASTIC LEUKEMIA)

Teaser

Summary

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.

Work performed

1.- 20 peer review publications (please see report for details)
2.- Three PhD dissertations (Damia Romero-Moya 2017, Cristina Prieto 2018, Oscar Navarro Montero 2017)
3.- One patent. PCT presented in August 2018.
Inventors: Cristina Prieto, Heleia Roca, BelÃ©n LÃ³pez-MillÃ¡n, Clara Bueno, Pablo MenÃ©ndez.
Title: NG2 antigen as a therapeutic target in MLL-rearranged acute leukemia
Reference Number: EP17382551.4 Country: EspaÃ±a Date: September 4th 2017
International Extension: PCT/P14748PC00 August 4th 2018
Property/Company/University: Institute Josep Carreras

4.- Funding being searched for a phase I clinical trial for cortical ALL in relapsing patients with or without prior alo-transplantation.

Final results

The main progress beyond the state of the art was the discovery that the NG2 antigen may be a therapeutic target for kids with B-ALL. Also, we developed different CAR T cells for targeting the leukemic cells of these patients. Work is submitted and funding is being searched for an academic phase I clinical trial.