Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis
Agraz-Doblás, Antonio (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Bueno, Clara (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Rogers, R. B. (Department of Medicine. University of Cambridge. Cambridge Biomedical Campus)
Roy, A. (Department of Paediatrics. University of Oxford)
Schneider, P. (Princess Maxima Center for Pediatric Oncology)
Bardini, Michela (Università degli Studi di Milano-Bicocca)
Ballerini, Paola (Pediatric Hematology. A. Trousseau Hospital)
Cazzaniga, Giovanni (Centro Ricerca Tettamanti. Department of Pediatrics. University of Milano Bicocca. Fondazione MBBM)
Moreno, T. (Instituto de Biomedicina y Biotecnología de Cantabria. Universidad de Cantabria-CSIC)
Revilla, C. (Instituto de Biomedicina y Biotecnología de Cantabria. Universidad de Cantabria-CSIC)
Gut, Marta (Universitat Pompeu Fabra)
Valsecchi, M. G. (Interfant Trial Data Center. University of Milano-Bicocca)
Roberts, I. (MRC Molecular Haematology Unit. MRC Weatherall Institute of Molecular Medicine. University of Oxford)
Pieters, R. (Princess Maxima Center for Pediatric Oncology)
De Lorenzo, P. (Interfant Trial Data Center. University of Milano-Bicocca)
Varela, Ignacio (Instituto de Biomedicina y Biotecnología de Cantabria. Universidad de Cantabria-CSIC)
Menéndez Bujan, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Stam, R. W. (Princess Maxima Center for Pediatric Oncology)
Universitat Autònoma de Barcelona

Date:	2019
Abstract:	Bcell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1 (MLL-AF4) infant B-cell acute lymphoblastic leukemia remains difficult to model, and the pathogenic contribution in cancer of the reciprocal fusions resulting from derivative translocated-chromosomes remains obscure. Here, "multi-layered" genome-wide analyses and validation were performed on a total of 124 de novo cases of infant B-cell acute lymphoblastic leukemia uniformly diagnosed and treated according to the Interfant 99/06 protocol. These patients showed the most silent mutational landscape reported so far for any sequenced pediatric cancer. Recurrent mutations were exclusively found in K-RAS and N-RAS, were subclonal and were frequently lost at relapse, despite a larger number of non-recurrent/non-silent mutations. Unlike non-MLL-rearranged B-cell acute lymphoblastic leukemias, B-cell receptor repertoire analysis revealed minor, non-expanded B-cell clones in t(4;11) infant B-cell acute lymphoblastic leukemia, and RNAsequencing showed transcriptomic similarities between t(4;11) infant B-cell acute lymphoblastic leukemias and the most immature human fetal liver hematopoietic stem and progenitor cells, confirming a "pre-VDJ" fetal cellular origin for both t(4;11) and RAS. The reciprocal fusion AF4-MLL was expressed in only 45% (19/43) of the t(4;11) patients, and HOXA cluster genes are exclusively expressed in AF4-MLL-expressing patients. Importantly, AF4-MLL/HOXA-expressing patients had a significantly better 4-year eventfree survival (62. 4% vs. 11. 7%, P=0. 001), and overall survival (73. 7 vs. 25. 2%, P=0. 016). AF4-MLL expression retained its prognostic significance when analyzed in a Cox model adjusting for risk stratification according to the Interfant-06 protocol based on age at diagnosis, white blood cell count and response to prednisone. This study has clinical implications for disease outcome and diagnostic risk-stratification of t(4;11) infant B-cell acute lymphoblastic leukemia.
Grants:	European Commission 646903 European Commission 637904 Ministerio de Economía y Competitividad SAF-SAF2013-43065 Ministerio de Economía y Competitividad SAF2016-76758-R Instituto de Salud Carlos III PI14-01191 Agència de Gestió d'Ajuts Universitaris i de Recerca SGR330
Note:	Altres ajuts: This work was supported by the Asociación Española Contra el Cáncer (AECC-CI-2015), FERO Foundation. PM/IV also acknowledge financial support from The Obra Social La Caixa-Fundaciò Josep Carreras, The Inocente Inocente Foundation and Fundación Ramón Areces.PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL).
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Biomarkers, Tumor ; Biopsy ; Bone Marrow ; Chromosome Aberrations ; Disease Susceptibility ; Gene Expression Profiling ; Gene Rearrangement ; Genome-Wide Association Study ; Genomic Instability ; Histone-Lysine N-Methyltransferase ; Homeodomain Proteins ; Humans ; In Situ Hybridization, Fluorescence ; Mutation ; Myeloid-Lymphoid Leukemia Protein ; Phosphatidylinositol 3-Kinases ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Ras Proteins ; Signal Transduction ; Survival Analysis ; V(D)J Recombination
Published in:	Haematologica, Vol. 104 Núm. 6 (2019) , p. 1176-1188, ISSN 1592-8721

DOI: 10.3324/haematol.2018.206375
PMID: 30679323

13 p, 4.7 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles