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Unraveling the Cellular Origin and Clinical Prognostic Markers of Infant B-cell Acute Lymphoblastic Leukemia Using Genome-Wide Analysis

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.

 Fuente: Haematologica, 104 (6), 1176-1188 Jun 2019

 Editorial: Ferrata Storti Foundation

 Año de publicación: 2019

 Nº de páginas: 13

 Tipo de publicación: Artículo de Revista

 DOI: 10.3324/haematol.2018.206375

 ISSN: 0390-6078,1592-8721

 Proyecto español: SAF2013- 43065 ; SAF2016-76758-R

 Url de la publicación: https://www.doi.org/10.3324/haematol.2018.206375

Autoría

AGRAZ-DOBLAS, ANTONIO

BUENO, CLARA

BASHFORD-ROGERS, RACHAEL

ROY, ANINDITA

SCHNEIDER, PAULINE

BARDINI, MICHELA

BALLERINI, PAOLA

CAZZANIGA, GIANNI

MORENO, THAIDY

CARLOS REVILLA GOMEZ

GUT, MARTA

VALSECCHI, MARIA G.

ROBERTS, IRENE

PIETERS, ROB

LORENZO, PAOLA DE

MENENDEZ, PABLO

STAM, RONALD W.