[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

ACUTE LYMPHOBLASTIC LEUKEMIA

Clinical and immunophenotypic characteristics of familial leukemia predisposition caused by PAX5 germline variants

Leukemia volume 36, pages 2338–2342 (2022)Cite this article

Subjects

Access through your institution
Buy or subscribe

The index case of Family 1 (Fig. 1A, III-3) is a boy from Ecuador who developed B-ALL at the age of 2 years and harbored the PAX5 c.547G>A p.Gly183Ser variant. The leukemia was classified as B-other ALL and molecular analysis revealed no fusion gene or hyperdiploidy. The patient was treated according to LAL-SHOP-2005 and achieved complete remission. Unfortunately, 9 years after the diagnosis, the patient had a bone marrow relapse. Then, he received salvage therapy (LAL/SEHOP-PETHEMA 2015) and reached complete remission. The genetic study of his relatives revealed the presence of the same germline PAX5 variant in his unaffected mother (II-2) and one of his healthy sisters (III-2), showing a reduced penetrance of the variant (33%) in analogy to the penetrance observed in Family 3 previously reported (Fig. 1A).

Family 2 is a Japanese family with a novel germline variant in PAX5, c.547G>C, p.Gly183Arg, in four relatives diagnosed with B-ALL (B-others type), amongst a monozygotic twin pair. The variant was detected in three affected siblings and an uncle (Fig. 1A, III-1, III-2, III-3, II-3) but was also present in their healthy mother and one healthy sibling (Fig. 1A, II-2, III-4), displaying a higher phenotype penetrance (60%, monozygotic twins are treated as one individual) than observed in patients with the PAX5 p.Gly183Ser variant. Although patient III-3 relapsed 2 years after completion of chemotherapy (CCLSG ALL2004), the patient was rescued by allogenic hematopoietic transplantation from an unrelated donor. Patients III-1 and III-2 were cured by conventional chemotherapy, and they maintained complete remission for more than 17 years.

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Genetic and immunophenotypic features of the families.

References

  1. Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat Genet. 2019;51:296–307.

    Article  CAS  Google Scholar 

  2. Porter CC. Germ line mutations associated with leukemias. Hematol Am Soc Hematol Educ Program. 2016;2016:302–8.

    Article  Google Scholar 

  3. Auer F, Ruschendorf F, Gombert M, Husemann P, Ginzel S, Izraeli S, et al. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia. 2014;28:1136–8.

    Article  CAS  Google Scholar 

  4. Shah S, Schrader KA, Waanders E, Timms AE, Vijai J, Miething C, 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 

  5. Yazdanparast S, Khatami SR, Galehdari H, Jaseb K. One missense mutation in exon 2 of the PAX5 gene in Iran. Genet Mol Res. 2015;14:17768–75.

    Article  CAS  Google Scholar 

  6. Duployez N, Jamrog LA, Fregona V, Hamelle C, Fenwarth L, Lejeune S, et al. Germline PAX5 mutation predisposes to familial B-cell precursor acute lymphoblastic leukemia. Blood. 2021;137:1424–8.

    Article  CAS  Google Scholar 

  7. Nakken S, Saveliev V, Hofmann O, Moller P, Myklebost O, Hovig E. Cancer Predisposition Sequencing Reporter (CPSR): a flexible variant report engine for high-throughput germline screening in cancer. Int J Cancer. 2021;149:1955–60.

    Article  CAS  Google Scholar 

  8. Wagener R, Taeubner J, Walter C, Yasin L, Alzoubi D, Bartenhagen C, et al. Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer. Eur J Hum Genet. 2021;29:1301–11.

    Article  CAS  Google Scholar 

  9. Urbanek P, Wang ZQ, Fetka I, Wagner EF, Busslinger M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell. 1994;79:901–12.

    Article  CAS  Google Scholar 

  10. Martin-Lorenzo A, Hauer J, Vicente-Duenas C, Auer F, Gonzalez-Herrero I, Garcia-Ramirez I, et al. Infection exposure is a causal factor in b-cell precursor acute lymphoblastic leukemia as a result of Pax5-inherited susceptibility. Cancer Disco. 2015;5:1328–43.

    Article  CAS  Google Scholar 

  11. Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural history. Blood. 2003;102:2321–33.

    Article  CAS  Google Scholar 

  12. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005;102:10604–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

AE and BP have been supported by CRIS Foundation to Beat Cancer https://criscancer.org/en/. MT was supported by Grants-in-Aid for Scientific Research 19H03614, and AMED 20ck0106467h0002. JH was supported by ERC Stg “PreventALL” 852222. This publication is based upon work from COST Action (CA16223; Working Group 3), supported by COST (European Cooperation in Science and Technology; https://www.cost.eu/).

Author information

Authors and Affiliations

  1. Department of Genetics, Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain

    Adela Escudero

  2. Translational Research Group in Pediatric Oncology, Hematopoietic Transplantation & Cell Therapy, Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain

    Adela Escudero, Barbara Pascual, María Vela & Antonio Pérez-Martínez

  3. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Masatoshi Takagi & Satoshi Miyamoto

  4. Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, Munich, Germany

    Franziska Auer & Julia Hauer

  5. Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital “Carl Gustav Carus”, Technical University Dresden (TUD), Dresden, Germany

    Ulrike Anne Friedrich

  6. Department of Pediatrics, Niigata Cancer Center, Niigata, Japan

    Atsushi Ogawa

  7. Department of Community Pediatrics, Perinatal and Maternal Medicine Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Kohsuke Imai

  8. Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Polina Stepensky

  9. Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, Duesseldorf, Germany

    Layal Yasin & Arndt Borkhardt

  10. Pediatric Hematology-Oncology, Schneider Children’s Medical Center and Sackler Faculty of Medicine, Tel-Aviv university, Tel-Aviv, Israel

    Sarah Elitzur

  11. Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain

    Antonio Pérez-Martínez

  12. Pediatric Department, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain

    Antonio Pérez-Martínez

Authors
  1. Adela Escudero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masatoshi Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Franziska Auer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrike Anne Friedrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoshi Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Atsushi Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kohsuke Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Barbara Pascual
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. María Vela
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Polina Stepensky
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Layal Yasin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sarah Elitzur
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Arndt Borkhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Antonio Pérez-Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Julia Hauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AE, MT, and JH conceived and designed the experiments; MT, FA, UAF, and LY performed molecular and cytogenetic analyses; SM and KI performed and analyzed immunological studies; AO, BP, MV, PS, SE, AB, and AP-M provided samples and clinical data; and AE, MT, FA, and JH wrote the manuscript with feedback from all authors.

Corresponding authors

Correspondence to Masatoshi Takagi or Julia Hauer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Escudero, A., Takagi, M., Auer, F. et al. Clinical and immunophenotypic characteristics of familial leukemia predisposition caused by PAX5 germline variants. Leukemia 36, 2338–2342 (2022). https://doi.org/10.1038/s41375-022-01661-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01661-7

This article is cited by

Search

Advanced search

Quick links