Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia

Elisabeth M P Steeghs,Aurélie Boeree,Hester A De Groot-Kruseman,Rob Pieters,Gabriele Escherich,Judith M Boer,Monique L Den Boer,Martin A Horstmann,Alex Q Hoogkamer,Valerie De Haas

doi:10.1038/s41598-019-41078-4

Abstract

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is associated with a high frequency of copy number alterations (CNAs) in IKZF1, EBF1, PAX5, CDKN2A/B, RB1, BTG1, ETV6, and/or the PAR1 region (henceforth: B-cell development genes). We aimed to gain insight in the association between CNAs in these genes, clinical outcome parameters, and cellular drug resistance. 71% of newly diagnosed pediatric BCP-ALL cases harbored one or more CNAs in these B-cell development genes. The distribution and clinical relevance of these CNAs was highly subtype-dependent. In the DCOG-ALL10 cohort, only loss of IKZF1 associated as single marker with unfavorable outcome parameters and cellular drug resistance. Prednisolone resistance was observed in IKZF1-deleted primary high hyperdiploid cells (~1500-fold), while thiopurine resistance was detected in IKZF1-deleted primary BCR-ABL1-like and non-BCR-ABL1-like B-other cells (~2.7-fold). The previously described risk stratification classifiers, i.e. IKZF1plus and integrated cytogenetic and CNA classification, both predicted unfavorable outcome in the DCOG-ALL10 cohort, and associated with ex vivo drug cellular resistance to thiopurines, or L-asparaginase and thiopurines, respectively. This resistance could be attributed to overrepresentation of BCR-ABL1-like cases in these risk groups. Taken together, our data indicate that the prognostic value of CNAs in B-cell development genes is linked to subtype-related drug responses.

Highlights

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children
A pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cohort of 515 newly diagnosed cases, representing all major ALL subtypes, was screened for copy number alterations (CNAs) in eight genes involved in transcription of lymphoid genes and the differentiation and proliferation of precursor B-cells (: B-cell development genes; Supplementary Fig. 1)
Deletions of the transcription factor IKZF1 were detected in 20% of the BCP-ALL cases

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The introduction of risk-adjusted treatment protocols has significantly improved survival rates, which nowadays is approaching 90% survival[1,2,3]. In addition to the major classifying abnormalities, secondary aberrations have been observed, including copy number alterations (CNAs) in genes involved in B-cell development (e.g. IKZF1, EBF1, PAX5, ETV6), cell cycle and proliferation (e.g. CDKN2A, CDKN2B, RB1, BTG1), and cytokine receptors (e.g. CRLF2)[4,5,8,9,13,14,15,16]. Some of these genetic lesions (e.g. IKZF1) were shown to predict clinical www.nature.com/scientificreports/. We performed an explorative study, which aimed to gain insight in associations between CNAs, cellular drug resistance, and clinical outcome

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