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LYMPHOBLASTIC LEUKEMIA

Germline PTPN13 mutations in patients with bone marrow failure and acute lymphoblastic leukemia

Leukemia volume 36, pages 2132–2135 (2022)Cite this article

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Acute lymphoblastic leukemia (ALL) is generally considered an acquired disorder and very few cases have been reported to be associated with germline mutations in PAX5, ETV6, and IKZF1 [1,2,3]. ALL has been observed in rare of inherited bone marrow failure sydnromes (IBMFSs) such as Fanocni anemia [4] and Shwachman-Diamond syndrome [5]. Identifying inherited causes of ALL may be critically important for selecting suitable therapeutic treatments, as applicable to conditions such as Fanoni anemia and ataxia telengeictasia which feature an increased sensitivity to ionizing radiation and chemotherapy.

Herein we report for the first time to our knowledge, germline mutations in protein tyrosine phosphatase non-receptor type 13 (PTPN13) in patients with ALL and/or an IBMFS, and interrogated the cellular effects of the mutations. PTPN13 is a protein tyrosine phosphatase (PTP) that regulates quiescence of hematopoietic stem cells and megakaryocytic differentiation via β-catenin [6, 7]. PTPN13 acts as a tumor suppressor gene and somatic loss of its function is associated with solid tumors [8].

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Fig. 1: Genetic investigation of two families with bone marrow failure and acute lymphoblastic leukemia.
Fig. 2: Mutations in PTPN13 decrease protein stability, decrease β-catenin levels and hinder megakaryocyte and erythroid differentiation.

Data availability

The data that supports the findings of this study is available upon request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

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Acknowledgements

The authors thank and acknowledge the patients and families for their participation in this study. Also, the authors would like to acknowledge the Care4Rare Research Consortium for identifying the mutation in the index case of Family A. The study was supported by grants from the Canadian Institutes of Health Research funding reference 286737 (YD), McLaughlin Centre Accelerator Grants in Genomic Medicine (YD and SWS), The Regional Government of Castile & Leon funding reference SA077P20 (AHH), and The Spanish Government funding reference PID2020–117692RB-I00 (AHH). The Care4Rare Canada Consortium work was funded by Genome Canada and the Ontario Genomics Institute (OGI147).

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Author notes

  1. These authors contributed equally: Houtan Moshiri, David A. Cabrera Riofrío, Yeon Jung Lim.

  2. These authors jointly supervised this work: Angel Hernández-Hernández, Yigal Dror.

Authors and Affiliations

  1. Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada

    Houtan Moshiri, Yeon Jung Lim, Supanun Lauhasurayotin, Santhosh Dhanraj, Richard N. Armstrong, Hongbing Li, Stephen W. Scherer & Yigal Dror

  2. Departmento Bioquímica y Biología Molecular, Universidad de Salamanca, 37008, Salamanca, Spain

    David A. Cabrera Riofrío & Angel Hernández-Hernández

  3. IBSAL (Instituto de Investigacion Biomedica de Salamanca), 37007, Salamanca, Spain

    David A. Cabrera Riofrío & Angel Hernández-Hernández

  4. Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada

    Yeon Jung Lim, Supanun Lauhasurayotin & Yigal Dror

  5. The Blood and Marrow Transplant, Hematology-Oncology Department, Dana-Dwek Children’s Hospital, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    Michal Manisterski & Ronit Elhasid

  6. Boston Children’s Hospital, Boston, MA, USA

    Francisco A. Bonilla

  7. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Santhosh Dhanraj & Yigal Dror

  8. McLaughlin Centre, University of Toronto, Toronto, ON, Canada

    Stephen W. Scherer

  9. Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Stephen W. Scherer

Authors
  1. Houtan Moshiri
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  2. David A. Cabrera Riofrío
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  3. Yeon Jung Lim
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  4. Supanun Lauhasurayotin
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  5. Michal Manisterski
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  6. Ronit Elhasid
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  8. Santhosh Dhanraj
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  9. Richard N. Armstrong
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  10. Hongbing Li
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  11. Stephen W. Scherer
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  12. Angel Hernández-Hernández
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  13. Yigal Dror
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Contributions

HM performed research, analyzed data, and wrote the paper. DACR performed research, analyzed data, and wrote the paper. YJL performed research, analyzed data, and wrote the paper. SL performed research, analyzed data, and wrote the paper. MM Provided data and samples, reviewed and edited the paper. RE Provided data and samples, reviewed and edited the paper. FAB performed research, provided data and samples, reviewed and edited the paper. SD performed research, analyzed data, and wrote the paper. RNA performed research, analyzed data, and wrote the paper. HL performed research and analyzed data, reviewed the paper. SWS assisted in the design of the study. AHH designed research, oversaw the project, analyzed data and wrote the paper. YD designed research, oversaw the project, analyzed data and wrote the paper.

Corresponding author

Correspondence to Yigal Dror.

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The authors have no financial competing interests that might be construed to influence the results or interpretation of their paper.

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Moshiri, H., Cabrera Riofrío, D.A., Lim, Y.J. et al. Germline PTPN13 mutations in patients with bone marrow failure and acute lymphoblastic leukemia. Leukemia 36, 2132–2135 (2022). https://doi.org/10.1038/s41375-022-01610-4

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