Effect of IKZF1 deletions on signal transduction pathways in Philadelphia chromosome negative pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Naomi E Van Der Sligte,Frank J G Scherpen,Victor Guryev,Arja Ter Elst,Eveline S J M De Bont,Frank N Van Leeuwen

doi:10.1186/s40164-015-0017-y

Abstract

BackgroundIKZF1 deletions are an unfavorable prognostic factor in children with Philadelphia chromosome positive (Ph+) as well as negative (Ph−) acute lymphoblastic leukemia (ALL). Although IKZF1 deletions occur in 10–15% of Ph− ALL cases, effects of IKZF1 deletions on signaling pathways in this group have not been extensively studied. Therefore, in this study we aimed to study the effect of IKZF1 deletions on active signal transduction pathways.MethodsMultiplex ligation-dependent probe amplification (MLPA) was used to determine IKZF1 deletions and other copy number alterations in 109 pediatric B-Cell Precursor ALL (BCP-ALL) patients. Kinase activity profiling of 45 primary Ph− BCP-ALL patients (31 IKZF1 wild type patients and 14 patients harboring an IKZF1 alteration) and western blot analysis of 14 pediatric BCP-ALL samples was performed to determine active signal transduction pathways.ResultsUnsupervised hierarchical cluster analysis of kinome profiles of 45 pediatric Ph− ALL cases showed no clustering based on IKZF1 status. Comparing the phosphorylation intensities of peptides associated with signaling pathways known to be involved in BCP-ALL maintenance, we did not observe differences between the two groups. Western blot analysis of 14 pediatric BCP-ALL samples showed large variations in phosphorylation levels between the different ALL samples, independent of IKZF1 status.ConclusionsBased on these results we conclude that, although IKZF1 deletions appear to be an important clinical prognostic factor, we were unable to identify a unique IKZF1 dependent protein expression signature in pediatric Ph− ALL and consequently no specific targets for future therapy of Ph−IKZF1 deleted BCP-ALL could be identified.Electronic supplementary materialThe online version of this article (doi:10.1186/s40164-015-0017-y) contains supplementary material, which is available to authorized users.

Highlights

IKZF1 deletions are an unfavorable prognostic factor in children with Philadelphia chromosome positive (Ph+) as well as negative (Ph−) acute lymphoblastic leukemia (ALL)
In this study we aimed to study the effect of IKZF1 deletions on active signal transduction pathways in Philadelphia negative pediatric B-Cell Precursor ALL (BCP-ALL) using kinome profiling
Generation of kinase activity profiles in IKZF1 deleted versus IKZF1 wild type Philadelphia negative pediatric BCP‐ALL Multiplex ligation-dependent probe amplification (MLPA) analysis revealed that among the 109 Philadelphia negative pediatric BCP-ALL patients tested, 17 (15.6%) patients harbor an IKZF1 deletion whereas one patient (0.9%) showed a gain of IKZF1

Summary

Introduction

IKZF1 deletions are an unfavorable prognostic factor in children with Philadelphia chromosome positive (Ph+) as well as negative (Ph−) acute lymphoblastic leukemia (ALL). Ikaros restricts the G1-S transition of the cell cycle when it binds to the DNA, by regulating transcription of cell cycle regulator genes e.g. a positive effect on cell cycle inhibitors CDKN1A (p21Cip1) and CDKN1B (p27Kip1) [11]. Ikaros can be phosphorylated by spleen tyrosine kinase (SYK) and bruton’s tyrosine kinase (BTK) [12, 13]. These phosphorylation events are essential for nuclear localization, regulation of DNA binding activity, and an optimal transcriptional function of Ikaros [12, 13]

Objectives

Methods

Results

Discussion

Conclusion