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Functional characterization of a germline ETV6 variant associated with inherited thrombocytopenia, acute lymphoblastic leukemia, and salivary gland carcinoma in childhood

International Journal of Hematology volume 112, pages 217–222 (2020)Cite this article

Abstract

Germline pathogenic ETV6 variants have been discovered in families with inherited thrombocytopenia and predisposition to hematological and solid malignancies. We present a patient with short stature who was initially diagnosed with chronic immune thrombocytopenia. Subsequently, the patient developed acute lymphoblastic leukemia, followed by mammary analog secretory carcinoma. Sequencing analysis identified an ETV6 c.641C > T (p.Pro214Leu) germline variant. The variant protein exhibited attenuated nuclear localization, increased protein degradation, and reduced transcription repression function. Our findings suggest that the ETV6 gene should be sequenced in patients with inherited thrombocytopenia and malignancy, and emphasize the importance of careful follow-up to identify secondary cancer in patients with pathogenic ETV6 variants.

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Abbreviations

ALL:

Acute lymphoblastic leukemia

FBS:

Fetal bovine serum

PBS:

Phosphate-buffered saline

ITP:

Immune thrombocytopenia

MDS:

Myelodysplastic syndrome

EBV-LCL:

EB virus-transformed lymphoblastoid cell line

MASC:

Mammary analog secretory carcinoma

MRI:

Magnetic resonance imaging

PET:

Positron emission tomography

WT:

Wild type

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Acknowledgements

The plasmids containing the human MMP3 and PF4 promoters cloned into pGL3 were a kind gift from Prof. Akiko Shimamura, Dana Farber and Boston Children’s Cancer. This research was supported by MEXT KAKENHI Grant Number JP19H03614 and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics.

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Author notes

  1. Hiroshi Yoshino and Yohei Nishiyama have contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Kyorin University, 181-8611 Shinkawa 6-20-2, Mitaka-Shi, Tokyo, Japan

    Hiroshi Yoshino, Kunimasa Yan & Fumio Bessho

  2. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), 113-8519 Yushima 1-5-45, Bukyo-ku, Tokyo, Japan

    Yohei Nishiyama, Tomohiro Morio & Masatoshi Takagi

  3. Department of Pathology, Kyorin University School of Medicine, 181-8611 Shinkawa 6-20-2, Mitaka-Shi, Tokyo, Japan

    Hiroshi Kamma, Tomohiro Chiba & Masachika Fujiwara

  4. Department of Otolaryngology Head and Neck Surgery, Kyorin University School of Medicine, 181-8611 Shinkawa 6-20-2, Mitaka-Shi, Tokyo, Japan

    Takehiro Karaho

  5. Department of Head and Neck Surgery, Saitama Medical University International Medical Center, 350-1298 Yamane 397-1, Hidaka-City, Saitama, Japan

    Yasunao Kogashiwa

Authors
  1. Hiroshi Yoshino
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  2. Yohei Nishiyama
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  3. Hiroshi Kamma
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  4. Tomohiro Chiba
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  5. Masachika Fujiwara
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  6. Takehiro Karaho
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  7. Yasunao Kogashiwa
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  8. Tomohiro Morio
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  9. Kunimasa Yan
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  10. Fumio Bessho
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  11. Masatoshi Takagi
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Corresponding author

Correspondence to Masatoshi Takagi.

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Yoshino, H., Nishiyama, Y., Kamma, H. et al. Functional characterization of a germline ETV6 variant associated with inherited thrombocytopenia, acute lymphoblastic leukemia, and salivary gland carcinoma in childhood. Int J Hematol 112, 217–222 (2020). https://doi.org/10.1007/s12185-020-02885-y

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  • DOI: https://doi.org/10.1007/s12185-020-02885-y

Keywords

  • ETV6
  • Germline
  • Acute lymphoblastic leukemia
  • Mammary analog secretory carcinoma
  • Short stature