Page 94 - 2019_06-Haematologica-web

Ferrata Storti Foundation
Haematologica 2019 Volume 104(6):1176-1188
Acute Lymphoblastic Leukemia
Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis
Antonio Agraz-Doblas,1,2 Clara Bueno,2# Rachael Bashford-Rogers,3# Anindita Roy,4,# Pauline Schneider,5 Michela Bardini,6 Paola Ballerini,7 Gianni Cazzaniga,6 Thaidy Moreno,1 Carlos Revilla,1 Marta Gut,8,9 Maria G. Valsecchi,10 Irene Roberts,4,11 Rob Pieters,5 Paola De Lorenzo,10 Ignacio Varela,1,$,* Pablo Menendez2,12,13,$,* and Ronald W. Stam5
1Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria- CSIC, Santander, Spain; 2Josep Carreras Leukemia Research Institute-Campus Clinic, Department of Biomedicine, School of Medicine, University of Barcelona, Spain; 3Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, UK; 4Department of Paediatrics, University of Oxford, UK; 5Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands; 6Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano Bicocca, Fondazione MBBM, Monza, Italy; 7Pediatric Hematology, A. Trousseau Hospital, Paris, France; 8CNAG-CRG, Center for Genomic Regulation, Barcelona, Spain; 9Universitat Pompeu Fabra, Barcelona, Spain; 10Interfant Trial Data Center, University of Milano-Bicocca, Monza, Italy; 11MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, UK; 12Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain and 13Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), ISCIII, Barcelona, Spain
#These authors contributed equally to this work. $These senior authors contributed equally to this work.
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 lym- phoblastic 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 muta- tions 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 RASmut. 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 ana- lyzed 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 out- come and diagnostic risk-stratification of t(4;11)+ infant B-cell acute lym- phoblastic leukemia.
Correspondence:
PABLO MENÉNDEZ
pmenendez@carrerasresearch.org
IGNACIO VARELA
Ignacio.varela@unican.es
Received: September 7, 2018. Accepted: December 20, 2018. Pre-published: January 24, 2019.
doi:10.3324/haematol.2018.206375
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/6/1176
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1176
haematologica | 2019; 104(6)
ARTICLE