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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

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.

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

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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/).

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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
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  2. Masatoshi Takagi
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  3. Franziska Auer
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  8. Barbara Pascual
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  9. María Vela
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  11. Layal Yasin
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  12. Sarah Elitzur
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  14. Antonio Pérez-Martínez
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  15. Julia Hauer
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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.

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Correspondence to Masatoshi Takagi or Julia Hauer.

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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

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