Skip to main content
SpringerLink
Log in

Germline Biology of Pediatric ALL

  • Chapter
  • First Online:
Pediatric Acute Lymphoblastic Leukemia

  • 992 Accesses

Abstract

Molecular genomic studies for ALL have been focused on somatically acquired genetic alterations in leukemic cells, and germline cells have been used mainly as a control to extract somatic mutation. However, recent studies demonstrated that germline genomics conferred pathogenesis of ALL, and an importance of genetic background in development of pediatric ALL is widely recognized. An association between polymorphism and adverse events has been already reported, and recent genomic analyses for familial ALL cases identified inherited causative genes for ALL. Moreover, some studies showed that a certain fraction of non-syndromic/non-familial ALL cases had pathogenic germline variants in cancer predisposition genes, such as ETV6, IKZF1, and TP53. These variants could contribute to not only poor response but also an increased risk of secondary neoplasms. Comprehensive understanding of biology in both ALL cells and germline cells is required.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019;105:1095–105.

    Google Scholar 

  2. Moriyama T, Nishii R, Lin TN, et al. The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics. 2017;27:236–9.

    Article  CAS  Google Scholar 

  3. Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol. 1989;7:1816–23.

    Article  CAS  Google Scholar 

  4. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990;336:225–9.

    Article  CAS  Google Scholar 

  5. Lennard L, Gibson BE, Nicole T, Lilleyman JS. Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child. 1993;69:577–9.

    Article  CAS  Google Scholar 

  6. Relling MV, Pui CH, Cheng C, Evans WE. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood. 2006;107:843–4.

    Article  CAS  Google Scholar 

  7. Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood. 1999;93:2817–23.

    Article  CAS  Google Scholar 

  8. Yang SK, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017–20.

    Article  CAS  Google Scholar 

  9. Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015;33:1235–42.

    Article  CAS  Google Scholar 

  10. Tanaka Y, Kato M, Hasegawa D, et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol. 2015;171(1):109–15.

    Article  CAS  Google Scholar 

  11. Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48:367–73.

    Article  CAS  Google Scholar 

  12. Tsujimoto S, Osumi T, Uchiyama M, et al. Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms. Leukemia. 2018;32:2710–4.

    Article  CAS  Google Scholar 

  13. Diouf B, Crews KR, Lew G, et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA. 2015;313:815–23.

    Article  CAS  Google Scholar 

  14. Kawedia JD, Kaste SC, Pei D, et al. Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2011;117:2340–7. quiz 2556

    Article  CAS  Google Scholar 

  15. Ben Tanfous M, Sharif-Askari B, Ceppi F, et al. Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia. Clin Cancer Res. 2015;21:329–34.

    Article  CAS  Google Scholar 

  16. Soh SX, Lim JY, Huang JW, Jiang N, Yeoh AE, Ong ST. Multi-agent chemotherapy overcomes glucocorticoid resistance conferred by a BIM deletion polymorphism in pediatric acute lymphoblastic leukemia. PLoS One. 2014;9:e103435.

    Article  Google Scholar 

  17. Tinhofer I, Marschitz I, Henn T, Egle A, Greil R. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2000;95:610–8.

    Article  CAS  Google Scholar 

  18. Cave H, Caye A, Strullu M, et al. Acute lymphoblastic leukemia in the context of RASopathies. Eur J Med Genet. 2016;59:173–8.

    Article  Google Scholar 

  19. van der Werff Ten Bosch J, van den Akker M. Genetic predisposition and hematopoietic malignancies in children: primary immunodeficiency. Eur J Med Genet. 2016;59:647–53.

    Article  Google Scholar 

  20. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242–52.

    Article  CAS  Google Scholar 

  21. Shah S, Schrader KA, Waanders E, et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet. 2013;45:1226–31.

    Article  CAS  Google Scholar 

  22. Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47:535–8.

    Article  CAS  Google Scholar 

  23. Boutboul D, Kuehn HS, Van de Wyngaert Z, et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest. 2018;128:3071–87.

    Article  Google Scholar 

  24. Perez-Garcia A, Ambesi-Impiombato A, Hadler M, et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood. 2013;122:2425–32.

    Article  CAS  Google Scholar 

  25. Urayama KY, Chokkalingam AP, Manabe A, Mizutani S. Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia. Int J Hematol. 2013;97:3–19.

    Article  Google Scholar 

  26. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet. 2009;41:1006–10.

    Article  CAS  Google Scholar 

  27. Trevino LR, Yang W, French D, et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet. 2009;41:1001–5.

    Article  CAS  Google Scholar 

  28. Migliorini G, Fiege B, Hosking FJ, et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood. 2013;122:3298–307.

    Article  CAS  Google Scholar 

  29. Sherborne AL, Hosking FJ, Prasad RB, et al. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat Genet. 2010;42:492–4.

    Article  CAS  Google Scholar 

  30. Perez-Andreu V, Roberts KG, Harvey RC, et al. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet. 2013;45:1494–8.

    Article  CAS  Google Scholar 

  31. Xu H, Yang W, Perez-Andreu V, et al. Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst. 2013;105:733–42.

    Article  CAS  Google Scholar 

  32. Moriyama T, Metzger ML, Wu G, et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 2015;16:1659–66.

    Article  CAS  Google Scholar 

  33. Churchman ML, Qian M, Te Kronnie G, et al. Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell. 2018;33(5):937–948.e8.

    Article  CAS  Google Scholar 

  34. Qian M, Cao X, Devidas M, et al. TP53 Germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol. 2018;36:591–9.

    Article  CAS  Google Scholar 

  35. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336–46.

    Article  CAS  Google Scholar 

  36. Porter CC, Druley TE, Erez A, et al. Recommendations for surveillance for children with leukemia-predisposing conditions. Clin Cancer Res. 2017;23:e14–22.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Transplantation and Cell Therapy, Children’s Cancer Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan

    Motohiro Kato

Authors
  1. Motohiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Motohiro Kato .

Editor information

Editors and Affiliations

  1. Department of Transplantation and Cell Therapy, Children’s Cancer, Center National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan

    Motohiro Kato

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kato, M. (2020). Germline Biology of Pediatric ALL. In: Kato, M. (eds) Pediatric Acute Lymphoblastic Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-15-0548-5_3

Download citation

  • DOI: https://doi.org/10.1007/978-981-15-0548-5_3

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-15-0547-8

  • Online ISBN: 978-981-15-0548-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation