期刊
HAEMATOLOGICA
卷 104, 期 6, 页码 1176-1188出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.206375
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资金
- Joint MRC/Wellcome Trust [MR/R006237/1]
- European Research Council [CoG-201-4646903, StG-2014-637904]
- Spanish Ministry of Economy and Competitiveness [SAF-SAF2013-43065, SAF2016-76758-R]
- Asociacion Espanola Contra el Cancer (AECC-CI-2015)
- FERO Foundation
- ISCIII [PI14-01191]
- Obra Social La Caixa-Fundacio Josep Carreras
- Inocente Inocente Foundation
- Fundacion Ramon Areces
- The Generalitat de Catalunya [SGR330]
- Programme Grant from Bloodwise [LLR 13001]
- Oxford NIHR Biomedical Centre based at Oxford University Hospitals NHS Trust and University of Oxford
- Bloodwise [14041]
- MRC [MR/R006237/1] Funding Source: UKRI
B-cell 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 similar to 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 RNA-sequencing 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(mut). 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 event-free 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.
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