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


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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Acute lymphoblastic leukemia


Fetal bovine serum


Phosphate-buffered saline


Immune thrombocytopenia


Myelodysplastic syndrome


EB virus-transformed lymphoblastoid cell line


Mammary analog secretory carcinoma


Magnetic resonance imaging


Positron emission tomography


Wild type


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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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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).

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