Home > Articles > Published articles > Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis |
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 |
13 p, 4.7 MB |