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J Pediatr Genet 2023; 12(04): 288-300
DOI: 10.1055/s-0041-1742246
Original Article

Genetic Profiling of Pediatric Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

Dilara Fatma Akin-Bali 
1   Department of Medical Biology, Faculty of Medicine, Niğde Ömer Halisdemir University, Niğde, Turkey
,
Beyza Doganay Erdogan 
2   Department of Biostatistic, Faculty of Medicine, Biostatistics, Ankara University, Ankara, Turkey
,
Deniz Aslar Oner 
3   Atatürk Vocational School of Health Services, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey
,
Akkan Mahmud 
4   LÖSANTE Children's and Adult Hospital, Ankara, Turkey
,
Serpil Tasdelen 
4   LÖSANTE Children's and Adult Hospital, Ankara, Turkey
,
Emin Kurekci 
4   LÖSANTE Children's and Adult Hospital, Ankara, Turkey
,
Nejat Akar 
5   Department of Pediatrics, TOBB-ETU Hospital, Ankara, Turkey
,
Hilal Ozdag Sevgili 
6   Ankara University Biotechnology Institute, Ankara, Turkey
› Author Affiliations Funding This work was supported by grants from the Scientific and Technological Research Council of Turkey (TUBITAK) (project no. 114S030) and Ankara University Scientific Research Projects Office (project no. 14L0415002).
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Abstract

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous leukemia subgroup. It has multiple sub-types that are likely to be classified by prognostic factors. Following a systematic literature review, this study analyzed the genes correlated with BCP-ALL prognosis (IKZF1, PAX5, EBF1, CREBBP, CRLF2, JAK2, ERG, CXCR4, ZAP70, VLA4, NF1, NR3C1, RB1, TSLP, ZNRF1, and FOXO3A), specifically their nucleotide variations and expression profiles in pediatric BCP-ALL samples. The study included 45 pediatric BCP-ALL patients with no cytogenetic anomaly and a control group of 10 children. The selected genes' hot-spot regions were sequenced using next-generation sequencing, while Polymorphism Phenotyping v2 and Supplemental Nutrition Assistance Program were used to identify pathogenic mutations. The expression analysis was performed using quantitative real-time polymerase chain reaction. The mutation analysis detected 328 variants (28 insertions, 47 indels, 74 nucleotide variants, 75 duplications, and 104 deletions). The most and least frequently mutated genes were IKZF1 and CREBBP, respectively. There were statistically significant differences between patients and controls for mutation distribution in eight genes (ERG, CRLF2, CREBBP, TSLP, JAK2, ZAP70, FOXO3A, and NR3C1). The expression analysis revealed that JAK and ERG were significantly overexpressed in patients compared with controls (respectively, p = 0.004 and p = 0.003). This study combined genes and pathways previously analyzed in pediatric BCP-ALL into one dataset for a comprehensive analysis from the same samples to unravel candidate prognostic biomarkers. Novel mutations were identified in all of the studied genes.

Keywords

pediatric BCP-ALL - mutation - gene expression - NGS - biomarker

Supplementary Material



Publication History

Received: 06 August 2021

Accepted: 09 December 2021

Article published online:
10 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Harrison CJ, Haas O, Harbott J. et al; Biology and Diagnosis Committee of International Berlin-Frankfürt-Münster study group. Detection of prognostically relevant genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: recommendations from the Biology and Diagnosis Committee of the International Berlin-Frankfürt-Münster study group. Br J Haematol 2010; 151 (02) 132-142
    CrossrefPubMedGoogle Scholar
  • 2 Mullighan CG. The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 174-180
    CrossrefPubMedGoogle Scholar
  • 3 Schwab CJ, Chilton L, Morrison H. et al. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica 2013; 98 (07) 1081-1088
    CrossrefPubMedGoogle Scholar
  • 4 Starý J, Zuna J, Zaliova M. New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia. F1000 Res 2018; 7: 7
    CrossrefPubMedGoogle Scholar
  • 5 Woo JS, Alberti MO, Tirado CA. Childhood B-acute lymphoblastic leukemia: a genetic update. Exp Hematol Oncol 2014; 3: 16
    CrossrefPubMedGoogle Scholar
  • 6 Reddy A, Espinoza I, Cole D. et al. Genetic mutations in B-acute lymphoblastic leukemia among African American and European American children. Clin Lymphoma Myeloma Leuk 2018; 18 (12) e501-e508
    CrossrefPubMedGoogle Scholar
  • 7 Vijayakrishnan J, Studd J, Broderick P. et al; PRACTICAL Consortium. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia. Nat Commun 2018; 9 (01) 1340
    CrossrefPubMedGoogle Scholar
  • 8 Firtina S, Sayitoglu M, Hatirnaz O. et al. Evaluation of PAX5 gene in the early stages of leukemic B cells in the childhood B cell acute lymphoblastic leukemia. Leuk Res 2012; 36 (01) 87-92
    CrossrefPubMedGoogle Scholar
  • 9 Liu YF, Wang BY, Zhang WN. et al. Genomic profiling of adult and pediatric B-cell acute lymphoblastic leukemia. EBioMedicine 2016; 8: 173-183
    CrossrefPubMedGoogle Scholar
  • 10 Shang Z, Zhao Y, Zhou K, Xu Y, Huang W. PAX5 alteration-associated gene-expression signatures in B-cell acute lymphoblastic leukemia. Int J Hematol 2013; 97 (05) 599-603
    CrossrefPubMedGoogle Scholar
  • 11 Ghazavi F, Lammens T, Van Roy N. et al. Molecular basis and clinical significance of genetic aberrations in B-cell precursor acute lymphoblastic leukemia. Exp Hematol 2015; 43 (08) 640-653
    CrossrefPubMedGoogle Scholar
  • 12 Mullighan CG. Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest 2012; 122 (10) 3407-3415
    CrossrefPubMedGoogle Scholar
  • 13 Kohlmann A, Klein HU, Weissmann S. et al. The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories. Leukemia 2011; 25 (12) 1840-1848
    CrossrefPubMedGoogle Scholar
  • 14 Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29 (09) e45
    CrossrefPubMedGoogle Scholar
  • 15 Dheda K, Huggett JF, Bustin SA, Johnson MA, Rook G, Zumla A. Validation of housekeeping genes for normalizing RNA expression in real-time PCR. Biotechniques 2004; 37 (01) 112-114
    CrossrefPubMedGoogle Scholar
  • 16 Lilljebjörn H, Fioretos T. New oncogenic subtypes in pediatric B-cell precursor acute lymphoblastic leukemia. Blood 2017; 130 (12) 1395-1401
    CrossrefPubMedGoogle Scholar
  • 17 Zhou Y, Kanagal-Shamanna R, Zuo Z, Tang G, Medeiros LJ, Bueso-Ramos CE. Advances in B-lymphoblastic leukemia: cytogenetic and genomic lesions. Ann Diagn Pathol 2016; 23: 43-50
    CrossrefPubMedGoogle Scholar
  • 18 van der Sligte NE, Scherpen FJ, Ter Elst A, Guryev V, van Leeuwen FN, de Bont ES. Effect of IKZF1 deletions on signal transduction pathways in Philadelphia chromosome negative pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Exp Hematol Oncol 2015; 4: 23
    CrossrefPubMedGoogle Scholar
  • 19 Waanders E, van der Velden VHJ, van der Schoot CE. 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 (02) 254-258
    CrossrefPubMedGoogle Scholar
  • 20 Mullighan CG, Su X, Zhang J. et al; Children's Oncology Group. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360 (05) 470-480
    CrossrefPubMedGoogle Scholar
  • 21 Dai YE, Tang L, Healy J, Sinnett D. Contribution of polymorphisms in IKZF1 gene to childhood acute leukemia: a meta-analysis of 33 case-control studies. PLoS One 2014; 9 (11) e113748
    CrossrefPubMedGoogle Scholar
  • 22 Heltemes-Harris LM, Willette MJ, Ramsey LB. et al. Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia. J Exp Med 2011; 208 (06) 1135-1149
    CrossrefPubMedGoogle Scholar
  • 23 Iacobucci I, Lonetti A, Paoloni F. et al. The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome. A report on behalf of the GIMEMA Acute Leukemia Working Party. Haematologica 2010; 95 (10) 1683-1690
    CrossrefPubMedGoogle Scholar
  • 24 Familiades J, Bousquet M, Lafage-Pochitaloff M. et al. PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study. Leukemia 2009; 23 (11) 1989-1998
    CrossrefPubMedGoogle Scholar
  • 25 Bhadri VA, Trahair TN, Lock RB. Glucocorticoid resistance in paediatric acute lymphoblastic leukaemia. J Paediatr Child Health 2012; 48 (08) 634-640
    CrossrefPubMedGoogle Scholar
  • 26 El-Fayoumi R, Hagras M, Abozenadaha A, Bawazir W, Shinawi T. Association between NR3C1 gene polymorphisms and toxicity induced by glucocorticoids therapy in Saudi children with acute lymphoblastic leukemia. Asian Pac J Cancer Prev 2018; 19 (05) 1415-1423
    PubMedGoogle Scholar
  • 27 Shinohara T, Urayama KY, Watanabe A. et al. Inherited genetic variants associated with glucocorticoid sensitivity in leukaemia cells. J Cell Mol Med 2020; 24 (22) 12920-12932
    CrossrefPubMedGoogle Scholar
  • 28 Tao Y, Williams-Skipp C, Scheinman RI. Mapping of glucocorticoid receptor DNA binding domain surfaces contributing to transrepression of NF-kappa B and induction of apoptosis. J Biol Chem 2001; 276 (04) 2329-2332
    CrossrefPubMedGoogle Scholar
  • 29 Haarman EG, Kaspers GJ, Pieters R, Rottier MM, Veerman AJ. Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia. Leukemia 2004; 18 (03) 530-537
    CrossrefPubMedGoogle Scholar
  • 30 Kaymak Cihan M, Karabulut HG, Yürür Kutlay N, Ilgın Ruhi H, Tükün A, Olcay L. Association between N363S and BclI polymorphisms of the glucocorticoid receptor gene (NR3C1) and glucocorticoid side effects during childhood acute lymphoblastic leukemia treatment. Turk J Haematol 2017; 34 (02) 151-158
    CrossrefPubMedGoogle Scholar
  • 31 Nicolaides NC, Charmandari E. Glucocorticoid resistance. Exp Suppl 2019; 111: 85-102
    PubMedGoogle Scholar
  • 32 Mullighan CG, Zhang J, Kasper LH. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 2011; 471 (7337): 235-239
    CrossrefPubMedGoogle Scholar
  • 33 Mullighan CG, Zhang J, Harvey RC. et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2009; 106 (23) 9414-9418
    CrossrefPubMedGoogle Scholar
  • 34 Harvey RC, Mullighan CG, Chen IM. et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 2010; 115 (26) 5312-5321
    CrossrefPubMedGoogle Scholar
  • 35 Roll JD, Reuther GW. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. Cancer Res 2010; 70 (19) 7347-7352
    CrossrefPubMedGoogle Scholar
  • 36 Schindler CW. Series introduction. JAK-STAT signaling in human disease. J Clin Invest 2002; 109 (09) 1133-1137
    CrossrefPubMedGoogle Scholar
  • 37 Konoplev S, Lu X, Konopleva M. et al. CRLF2-positive B-cell acute lymphoblastic leukemia in adult patients: a single-institution experience. Am J Clin Pathol 2017; 147 (04) 357-363
    CrossrefPubMedGoogle Scholar
  • 38 Rashed RA, Kadry DY, El Taweel M, Abd El Wahab N, Abd El Hameed T. Relation of BAALC and ERG gene expression with overall survival in acute myeloid leukemia cases. Asian Pac J Cancer Prev 2015; 16 (17) 7875-7882
    CrossrefPubMedGoogle Scholar
  • 39 Siddique HR, Rao VN, Lee L, Reddy ES. Characterization of the DNA binding and transcriptional activation domains of the erg protein. Oncogene 1993; 8 (07) 1751-1755
    PubMedGoogle Scholar
  • 40 Qian M, Xu H, Perez-Andreu V. et al. Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics. Blood 2019; 133 (07) 724-729
    CrossrefPubMedGoogle Scholar