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Gene expression signatures and ex vivo drug sensitivity profiles in children with acute lymphoblastic leukemia

  • Human Genetics • Original Paper
  • Published:
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Abstract

Introduction

Causes of treatment failure in acute lymphoblastic leukemia (ALL) are still poorly understood. Microarray technology gives new possibilities for the analysis of the biology of leukemias. We hypothesize that drug sensitivity in pediatric ALL is driven by specific molecular mechanisms that correlate with gene expression profiles assessed by microarray analysis.

Objective

The aim of the study was to determine the ex vivo resistance profiles of 20 antileukemic drugs and gene expression profiles, with relation to response to initial therapy.

Patients and methods

Lymphoblasts were analyzed after bone marrow biopsy was obtained from 56 patients. The profile of in vitro resistance to drugs was determined in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) cytotoxicity assay. High-quality total RNA was prepared and hybridized to oligonucleotide arrays HG-U133A 2.0 Chip (Affymetrix). The expression of selected genes was tested by qualitative reverse transcription polymerase chain reaction (qRT-PCR).

Results and conclusions

The exposure of leukemic blasts to drugs initiates a complex cellular response, which reflects global changes in gene expression. Changes in the expression of several genes are highly correlated with drug resistance.

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References

  • Arceci RJ (1993) Clinical significance of P-glycoprotein in multidrug resistance malignancies. Blood 81:2215–2222

    PubMed  CAS  Google Scholar 

  • Bachman KE, Argani P, Samuels Y et al (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775

    Article  PubMed  CAS  Google Scholar 

  • Bhojwani D, Kang H, Menezes RX et al (2008) Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children’s Oncology Group Study. J Clin Oncol 26:4376–4384

    Article  PubMed  CAS  Google Scholar 

  • Blohm DH, Guiseppi-Elie A (2001) New developments in microarray technology. Curr Opin Biotechnol 12:41–47

    Article  PubMed  CAS  Google Scholar 

  • Brown JR, Auger KR (2011) Phylogenomics of phosphoinositide lipid kinases: perspectives on the evolution of second messenger signaling and drug discovery. BMC Evol Biol 11:4

    Article  PubMed  CAS  Google Scholar 

  • Cheok MH, Yang W, Pui CH et al (2003) Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nat Genet 34:85–90

    Article  PubMed  CAS  Google Scholar 

  • den Boer ML, Pieters R, Kazemier KM et al (1998) Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. Blood 91:2092–2098

    Google Scholar 

  • den Boer ML, Harms DO, Pieters R et al (2003) Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. J Clin Oncol 21:3262–3268

    Article  Google Scholar 

  • Evans WE, Relling MV (2004) Moving towards individualized medicine with pharmacogenomics. Nature 429:464–468

    Article  PubMed  CAS  Google Scholar 

  • Ferrando AA, Neuberg DS, Staunton J et al (2002) Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1:75–87

    Article  PubMed  CAS  Google Scholar 

  • Garza-González E, Bosques-Padilla FJ, Pérez-Pérez GI et al (2004) Association of gastric cancer, HLA-DQA1, and infection with Helicobacter pylori CagA+ and VacA+ in a Mexican population. J Gastroenterol 39:1138–1142

    Article  PubMed  Google Scholar 

  • Györffy B, Surowiak P, Kiesslich O et al (2006) Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer 118:1699–1712

    Article  PubMed  Google Scholar 

  • Hoelzer D, Gökbuget N, Ottmann O et al (2002) Acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 162–192

  • Hofmann WK, de Vos S, Elashoff D et al (2002) Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet 359:481–486

    Article  PubMed  CAS  Google Scholar 

  • Holleman A, Cheok MH, den Boer ML et al (2004) Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 351:533–542

    Article  PubMed  CAS  Google Scholar 

  • Holleman A, den Boer ML, de Menezes RX et al (2006) The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia. Blood 107:769–776

    Article  PubMed  CAS  Google Scholar 

  • Ikenoue T, Kanai F, Hikiba Y et al (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567

    Article  PubMed  CAS  Google Scholar 

  • Jarzab B, Gubała E, Lange D (2005) DNA microarrays and papillary thyroid carcinoma gene expression profile. Endokrynol Pol 56:293–301

    PubMed  Google Scholar 

  • Jeha S, Pui CH (2009) Risk-adapted treatment of pediatric acute lymphoblastic leukemia. Hematol Oncol Clin North Am 23:973–990

    Article  PubMed  Google Scholar 

  • Lugthart S, Cheok MH, den Boer ML et al (2005) Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemia. Cancer Cell 7:375–386

    Article  PubMed  CAS  Google Scholar 

  • McLennan AG (2006) The Nudix hydrolase superfamily. Cell Mol Life Sci 63:123–143

    Article  PubMed  CAS  Google Scholar 

  • Mildvan AS, Xia Z, Azurmendi HF et al (2005) Structures and mechanisms of Nudix hydrolases. Arch Biochem Biophys 433:129–143

    Article  PubMed  CAS  Google Scholar 

  • Möricke A, Reiter A, Zimmermann M et al (2008) Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111:4477–4489

    Article  PubMed  Google Scholar 

  • Möricke A, Zimmermann M, Reiter A et al (2010) Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 24:265–284

    Article  PubMed  Google Scholar 

  • Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  PubMed  CAS  Google Scholar 

  • Planelles D, Nagore E, Moret A et al (2006) HLA class II polymorphisms in Spanish melanoma patients: homozygosity for HLA-DQA1 locus can be a potential melanoma risk factor. Br J Dermatol 154:261–266

    Article  PubMed  CAS  Google Scholar 

  • Pui CH (2009) Toward a total cure for acute lymphoblastic leukemia. J Clin Oncol 27:5121–5123

    Article  PubMed  Google Scholar 

  • Pui CH, Campana D, Pei D et al (2009) Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360:2730–2741

    Article  PubMed  CAS  Google Scholar 

  • Riemersma SA, Jordanova ES, Schop RF et al (2000) Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites. Blood 96:3569–3577

    PubMed  CAS  Google Scholar 

  • Samuels Y, Ericson K (2006) Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18:77–82

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  PubMed  CAS  Google Scholar 

  • Schotte D, Pieters R, Den Boer ML (2011a) MicroRNAs in acute leukemia: from biological players to clinical contributors. Leukemia (in press). doi:10.1038/leu.2011.151

  • Schotte D, De Menezes RX, Moqadam FA et al (2011b) MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia. Haematologica 96:703–711

    Article  PubMed  Google Scholar 

  • Shah AA, Meese E, Blin N (2010) Profiling of regulatory microRNA transcriptomes in various biological processes: a review. J Appl Genet 51:501–507

    Article  PubMed  CAS  Google Scholar 

  • Staal FJ, de Ridder D, Szczepanski T et al (2010) Genome-wide expression analysis of paired diagnosis-relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype. Leukemia 24:491–499

    Article  PubMed  CAS  Google Scholar 

  • Styczyński J, Wysocki M (2004) Is the in vitro drug resistance profile the strongest prognostic factor in childhood acute lymphoblastic leukemia? J Clin Oncol 22:963–964

    Article  PubMed  Google Scholar 

  • Styczynski J, Pieters R, Huismans DR et al (2000) In vitro drug resistance profiles of adult versus childhood acute lymphoblastic leukaemia. Br J Haematol 110:813–818

    Article  PubMed  CAS  Google Scholar 

  • Styczynski J, Wysocki M, Debski R et al (2002) Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia. Leuk Lymphoma 43:1843–1848

    Article  PubMed  CAS  Google Scholar 

  • Styczynski J, Wysocki M, Dluzniewska A et al (2008) Prognostic impact of combined fludarabine, treosulfan and mitoxantrone resistance profile in childhood acute myeloid leukemia. Anticancer Res 28:1927–1931

    PubMed  CAS  Google Scholar 

  • Szczepanek J, Styczyński J, Haus O et al (2007) Gene expression profiles in acute lymphoblastic leukemia in children and adults. Postepy Hig Med Dosw (Online) 61:519–533

    Google Scholar 

  • Thomas H, Coley HM (2003) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 10:159–165

    PubMed  Google Scholar 

  • van den Heuvel-Eibrink MM, Sonneveld P, Pieters R (2000) The prognostic significance of membrane transport-associated multidrug resistance (MDR) proteins in leukemia. Int J Clin Pharmacol Ther 38:94–110

    PubMed  Google Scholar 

  • Vigorito E, Billadeu DD, Savoy D et al (2003) RhoG regulates gene expression and the actin cytoskeleton in lymphocytes. Oncogene 22:330–342

    Article  PubMed  CAS  Google Scholar 

  • Vilar E, Mukherjee B, Kuick R et al (2009) Gene expression patterns in mismatch repair-deficient colorectal cancers highlight the potential therapeutic role of inhibitors of the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway. Clin Cancer Res 15:2829–2839

    PubMed  CAS  Google Scholar 

  • Willenbrock H, Juncker AS, Schmiegelow K et al (2004) Prediction of immunophenotype, treatment response, and relapse in childhood acute lymphoblastic leukemia using DNA microarrays. Leukemia 18:1270–1277

    Article  PubMed  CAS  Google Scholar 

  • Yeoh EJ, Ross ME, Shurtleff SA et al (2002) Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1:133–143

    Article  PubMed  CAS  Google Scholar 

  • Zaza G, Cheok M, Yang W et al (2005) Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment. Blood 106:1778–1785

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Grant MNiSW No. N407 078 32/2964 and Grant UMK 10/2009.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

    Joanna Szczepanek, Monika Pogorzala, Mariusz Wysocki & Jan Styczynski

  2. Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Torun, Poland

    Joanna Szczepanek & Andrzej Tretyn

  3. Department of Clinical and Experimental Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland

    Michal Jarzab

  4. Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland

    Malgorzata Oczko-Wojciechowska, Malgorzata Kowalska & Barbara Jarzab

  5. Department of Clinical Genetics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

    Olga Haus

  6. Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, ul. Gagarina 9, 87-100, Torun, Poland

    Joanna Szczepanek

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  1. Joanna Szczepanek
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  2. Michal Jarzab
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Correspondence to Joanna Szczepanek.

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Szczepanek, J., Jarzab, M., Oczko-Wojciechowska, M. et al. Gene expression signatures and ex vivo drug sensitivity profiles in children with acute lymphoblastic leukemia. J Appl Genetics 53, 83–91 (2012). https://doi.org/10.1007/s13353-011-0073-x

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  • DOI: https://doi.org/10.1007/s13353-011-0073-x

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