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Haematologica 2019 Volume 104(7):1396-1406
Acute Lymphoblastic Leukemia
Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort
Marketa Zaliova,1,2,3 Jan Stuchly,1,2 Lucie Winkowska,1,2 Alena Musilova,1,2
Karel Fiser,1,2 Martina Slamova,1,2 Julia Starkova,1,2 Martina Vaskova,1,2
Ondrej Hrusak,1,2,3 Lucie Sramkova,1,2,3 Jan Stary,2,3 Jan Zuna1,2,3 and Jan Trka1,2,3
1CLIP - Childhood Leukaemia Investigation Prague; 2Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and 3University Hospital Motol, Prague, Czech Republic
ABSTRACT
Novel biological subtypes and clinically important genetic aberrations (druggable lesions, prognostic factors) have been described in B- other acute lymphoblastic leukemia (ALL) during the last decade; however, due to a lack of studies on unselected cohorts, their population frequency and mutual associations still have to be established. We studied 110 consecutively diagnosed and uniformly treated childhood B-other patients using single nucleotide polymorphism arrays and whole exome/transcriptome sequencing. The frequency of DUX4-rearranged, BCR-ABL1-like, ZNF384-rearranged, ETV6-RUNX1-like, iAMP21 and MEF2D-rearranged subtypes was 27%, 15%, 5%, 5%, 4%, and 2%, respectively; 43% of cases were not classified into any of these subtypes (B-rest). We found worse early response to treatment in DUX4-rearranged leukemia and a strong association of ZNF384-rearranged leukemia with B-myeloid immunophenotype. Of the druggable lesions, JAK/STAT-class and RAS/RAF/MAPK-class aberrations were found in 21% and 43% of patients, respectively; an ABL-class aberration was found in one patient. A recently described negative prognostic factor, IKZF1plus, was found in 14% of patients and was enriched in (but not exclusive for) BCR-ABL1-like sub- type. PAX5 fusions (including 4 novel), intragenic amplifications and P80R mutations were mutually exclusive and only occurred in the B-rest subset, altogether accounting for 20% of the B-other group. PAX5 P80R was asso- ciated with a specific gene expression signature, potentially defining a novel leukemia subtype. Our study shows unbiased European population-based frequencies of novel ALL subtypes, recurrent (cyto)genetic aberrations and their mutual associations. This study also strengthens and widens the cur- rent knowledge of B-other ALL and provides an objective basis for opti- mization of current genetic diagnostics.
Introduction
Knowledge about the genetics of pediatric B-cell precursor (BCP) acute lym- phoblastic leukemia (ALL) has grown substantially in the past decade due to the boom in genome-wide technologies. Some of the most important novel findings concern B-other ALL, a heterogeneous group of BCP-ALL with previously unknown genetic backgrounds, usually defined by the absence of all routinely assessed classifying aberrations. Several subtypes have been described within B- other ALL based on the presence of unique (presumably primary) genetic aberra- tions [iAMP21 ALL,1 DUX4 rearranged (r) ALL,2 ZNF384r ALL,3,5,6 MEF2Dr ALL3,6,7] or gene expression signatures (BCR-ABL1-like ALL8-10 and ETV6-RUNX1-like ALL2,11). Although the classification of BCP-ALL has been substantially refined, it is complicated by a partial overlap of some of these subtypes and/or their imperfect definitions. It has been shown that a significant proportion of iAMP21 ALL have
Correspondence:
JAN TRKA/MARKETA ZALIOVA
jan.trka@lfmotol.cuni.cz/ marketa.zaliova@lfmotol.cuni.cz
Received: August 21, 2018. Accepted: December 20, 2018. Pre-published: January 10, 2019.
doi:10.3324/haematol.2018.204974
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1396
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