Unraveling the Cellular Origin and Clinical Prognostic Markers of Infant B-cell Acute Lymphoblastic Leukemia Using Genome-Wide Analysis
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Agraz-Doblas, Antonio; Bueno, Clara; Bashford-Rogers, Rachael; Roy, Anindita; Schneider, Pauline; Bardini, Michela; Ballerini, Paola; Cazzaniga, Gianni; Moreno, Thaidy; Revilla Gómez, Carlos; Gut, Marta; Valsecchi, Maria G.; Roberts, Irene; Pieters, Rob; Lorenzo, Paola De; Varela Egocheaga, Ignacio; Menendez, Pablo; Stam, Ronald W.Fecha
2019Derechos
© Ferrata Storti Foundation.Agraz-Doblas, Antonio, et al. «Unraveling the Cellular Origin and Clinical Prognostic Markers of Infant B-Cell Acute Lymphoblastic Leukemia Using Genome-Wide Analysis». Haematologica, vol. 104, n.o 6, junio de 2019, pp. 1176-88. doi:10.3324/haematol.2018.206375. Obtained from the Haematologica Journal website http://www.haematologica.org
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Haematologica, 104 (6), 1176-1188 Jun 2019
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Ferrata Storti Foundation
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Resumen/Abstract
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 ~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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Excepto si se señala otra cosa, la licencia del ítem se describe como © Ferrata Storti Foundation.Agraz-Doblas, Antonio, et al. «Unraveling the Cellular Origin and Clinical Prognostic Markers of Infant B-Cell Acute Lymphoblastic Leukemia Using Genome-Wide Analysis». Haematologica, vol. 104, n.o 6, junio de 2019, pp. 1176-88. doi:10.3324/haematol.2018.206375. Obtained from the Haematologica Journal website http://www.haematologica.org