Experimental Hematology & Oncology | |
Effect of IKZF1 deletions on signal transduction pathways in Philadelphia chromosome negative pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) | |
Eveline S J M de Bont2  Frank N van Leeuwen1  Victor Guryev3  Arja ter Elst2  Frank J G Scherpen2  Naomi E van der Sligte2  | |
[1] Laboratory of Pediatric Oncology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands;Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, The Netherlands;European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands | |
关键词: Kinome profiling; Signaling; IKZF1; Acute lymphoblastic leukemia; | |
Others : 1224082 DOI : 10.1186/s40164-015-0017-y |
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received in 2015-07-24, accepted in 2015-07-27, 发布年份 2015 | |
【 摘 要 】
Background
IKZF1 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.
Methods
Multiplex 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.
Results
Unsupervised 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.
Conclusions
Based 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.
【 授权许可】
2015 van der Sligte et al.
【 预 览 】
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Fig.1. | 91KB | Image | download |
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【 参考文献 】
- [1]Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013; 381:1943-1955.
- [2]Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB et al.. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009; 360:470-480.
- [3]Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, Scheijen B et al.. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia. 2010; 24:1258-1264.
- [4]van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ et al.. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013; 122:2622-2629.
- [5]Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA et al.. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2009; 106:9414-9418.
- [6]Olsson L, Albitar F, Castor A, Behrendtz M, Biloglav A, Paulsson K et al.. Cooperative genetic changes in pediatric B-cell precursor acute lymphoblastic leukemia with deletions or mutations of IKZF1. Genes Chromosom Cancer. 2015; 54:315-325.
- [7]Olsson L, Johansson B. Ikaros and leukaemia. Br J Haematol. 2015; 169:479-491.
- [8]Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S et al.. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994; 79:143-156.
- [9]Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, Bigby M et al.. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity. 1996; 5:537-549.
- [10]Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995; 83:289-299.
- [11]Gomez-del Arco P, Maki K, Georgopoulos K. Phosphorylation controls Ikaros’s ability to negatively regulate the G(1)-S transition. Mol Cell Biol. 2004; 24:2797-2807.
- [12]Uckun FM, Ma H, Zhang J, Ozer Z, Dovat S, Mao C et al.. Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros. Proc Natl Acad Sci USA. 2012; 109:18072-18077.
- [13]Ma H, Qazi S, Ozer Z, Zhang J, Ishkhanian R, Uckun FM. Regulatory phosphorylation of Ikaros by Bruton’s tyrosine kinase. PLoS One. 2013; 8:e71302.
- [14]Dupuis A, Gaub MP, Legrain M, Drenou B, Mauvieux L, Lutz P et al.. Biclonal and biallelic deletions occur in 20% of B-ALL cases with IKZF1 mutations. Leukemia. 2013; 27:503-507.
- [15]Sun L, Liu A, Georgopoulos K. Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J. 1996; 15:5358-5369.
- [16]Sikkema AH, Diks SH, den Dunnen WF, ter Elst A, Scherpen FJ, Hoving EW et al.. Kinome profiling in pediatric brain tumors as a new approach for target discovery. Cancer Res. 2009; 69:5987-5995.
- [17]Ter Elst A, Diks SH, Kampen KR, Hoogerbrugge PM, Ruijtenbeek R, Boender PJ et al.. Identification of new possible targets for leukemia treatment by kinase activity profiling. Leuk Lymphoma. 2011; 52:122-130.
- [18]Kampen KR, Ter Elst A, Mahmud H, Scherpen FJ, Diks SH, Peppelenbosch MP et al.. Insights in dynamic kinome reprogramming as a consequence of MEK inhibition in MLL-rearranged AML. Leukemia. 2014; 28:589-599.
- [19]van der Sligte NE, Scherpen FJ, Meeuwsen-de Boer TG, Lourens HJ, Ter Elst A, Diks SH et al.. Kinase activity profiling reveals active signal transduction pathways in pediatric acute lymphoblastic leukemia: a new approach for target discovery. Proteomics. 2015; 15:1245-1254.
- [20]Iacobucci I, Iraci N, Messina M, Lonetti A, Chiaretti S, Valli E et al.. IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia. PLoS One. 2012; 7:e40934.
- [21]Safavi S, Hansson M, Karlsson K, Biloglav A, Johansson B, Paulsson K. Novel gene targets detected by genomic profiling in a consecutive series of 126 adults with acute lymphoblastic leukemia. Haematologica. 2015; 100:55-61.
- [22]Trageser D, Iacobucci I, Nahar R, Duy C, von Levetzow G, Klemm L et al.. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. J Exp Med. 2009; 206:1739-1753.
- [23]Dokter WH, Tuyt L, Sierdsema SJ, Esselink MT, Vellenga E. The spontaneous expression of interleukin-1 beta and interleukin-6 is associated with spontaneous expression of AP-1 and NF-kappa B transcription factor in acute myeloblastic leukemia cells. Leukemia. 1995; 9:425-432.
- [24]Waanders E, van der Velden VH, van der Schoot CE, van Leeuwen FN, van Reijmersdal SV, de Haas V et al.. Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia. Leukemia. 2011; 25:254-258.
- [25]Bill A, Schmitz A, Albertoni B, Song JN, Heukamp LC, Walrafen D et al.. Cytohesins are cytoplasmic ErbB receptor activators. Cell. 2010; 143:201-211.
- [26]Pan T, Sun J, Hu J, Hu Y, Zhou J, Chen Z et al.. Cytohesins/ARNO: the function in colorectal cancer cells. PLoS One. 2014; 9:e90997.
- [27]Irwin ME, Nelson LD, Santiago-O’Farrill JM, Knouse PD, Miller CP, Palla SL et al.. Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia. PLoS One. 2013; 8:e70608.
- [28]Lee JW, Soung YH, Kim SY, Nam SW, Park WS, Lee JY et al.. Kinase domain mutation of ERBB family genes is uncommon in acute leukemias. Leuk Res. 2006; 30:241-242.
- [29]Vitanza NA, Zaky W, Blum R, Meyer JA, Wang J, Bhatla T et al.. Ikaros deletions in BCR-ABL-negative childhood acute lymphoblastic leukemia are associated with a distinct gene expression signature but do not result in intrinsic chemoresistance. Pediatr Blood Cancer. 2014; 61:1779-1785.
- [30]Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST et al.. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009; 10:125-134.
- [31]Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D et al.. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014; 371:1005-1015.