Polyclonal evolution of lymphoproliferative disorders in XLP1
X-linked lymphoproliferative syndrome type 1 (XLP1) is an inborn error of immunity caused by pathogenic variants in SH2D1A and is frequently complicated by Epstein-Barr virus (EBV)–associated lymphoproliferative disorders (LPDs). However, cases of LPD without EBV infection have been reported and remain poorly understood. We investigated tumorigenesis mechanisms through transcriptomic profiling and somatic variant analysis in tumor samples from six patients with XLP1. Pathogenic variants were identified in two: one developed two distinct LPDs harboring CARD11/GNA13 and MECOM variants, while the other carried IRF4, P2RY8, KRAS, and CCND3 variants. Transcriptome analysis of three tumors, compared with diffuse large B cell lymphoma from patients without an underlying immune defect, revealed a distinct expression profile. Gene Ontology analysis showed upregulation of adaptive immune response genes, including various IgH and TCR genes, suggesting polyclonal lymphocyte proliferation. Overall, LPD associated with XLP1 may originate from polyclonal lymphocyte expansion, either in the presence or absence of EBV infection, and subsequently progress to malignancy through somatic variants.
Authors
- Masatoshi Takagi (ORCID: https://orcid.org/0000-0002-7580-9184)
- Akihiro Hoshino (ORCID: https://orcid.org/0000-0002-4392-0988)
- Yasuhiro Ikawa (ORCID: https://orcid.org/0000-0001-7204-1766)
- Areum Shin (ORCID: https://orcid.org/0000-0003-3341-0447)
- Dan Tomomasa (ORCID: https://orcid.org/0009-0003-3236-5098)
- Hirokazu Kanegane (ORCID: https://orcid.org/0000-0002-8696-9378)
- Takashi Taga (ORCID: https://orcid.org/0000-0003-0525-4766)
- Tomohiro Morio (ORCID: https://orcid.org/0000-0002-9259-1025)
- Yuta Sakai
- Keon Hee Yoo (ORCID: https://orcid.org/0000-0002-5980-7912)
- Naoki Sakata (ORCID: https://orcid.org/0000-0003-3522-3995)
- Doo Ri Kim (ORCID: https://orcid.org/0000-0001-5233-4043)
- Toshiaki Ishida (ORCID: https://orcid.org/0000-0002-8327-1089)
- Yui Namikawa
- Kenichi Yoshida
- Kenichi Sakamoto
- Akira Nishimura
- Seishi Ogawa
- Yae-Jean Kim
Institutions
- Kanazawa University (JP)
- Shinshu University (JP)
- Shiga University of Medical Science (JP)
- Kanazawa Medical University (JP)
- Kyoto University (JP)
- Samsung Medical Center (KR)
- Tokyo Institute of Psychiatry (JP)
- Kobe Children's Hospital (JP)
- Shinshu University Hospital (JP)
- National Center For Child Health and Development (JP)
- National Cancer Research Institute (GB)
- Kindai University (JP)
Publication Details
- Journal
- Journal of Human Immunity
- Published
- 2026-01-08
- DOI
- https://doi.org/10.70962/jhi.20250202
- Primary Topic
- Viral-associated cancers and disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00