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CYTOGENETICS AND MOLECULAR GENETICS

Molecular mechanisms underlying transformation of large granular lymphocytic leukemia to high-grade T-cell lymphoma

Leukemia volume 37, pages 1567–1571 (2023)Cite this article

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Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder divided into two main subtypes, with a T or NK phenotype [1, 2]. The clinical course of LGLL is usually indolent and transformation to high-grade T-cell lymphoma is extremely rare with few cases reported in the literature [3,4,5]. The molecular mechanism triggering this type of progression is not well understood. Here, we report two cases of T-LGLL transformation investigated with consecutive whole exome sequencing (WES) and TCRB locus rearrangement sequencing.

The second patient, a 61-year-old man, was investigated in 2018 for asymptomatic chronic neutropenia (0.7 × 109/l) and mild thrombocytopenia (96 × 109/l). We identified a CD8-LGL T clone harboring a STAT3 p.D661N mutation. After 3-years with no prior treatment, the patient received methotrexate, then Cytoxan for 6 months resulting in partial response (persistent thrombocytopenia and 16% of LGLs on blood count). While still on treatment, the patient complained of right hip pain and B symptoms. PET scan showed a large hypermetabolic lesion in the right femoral head and multiple lymphadenopathies (Fig. 1F). The bone biopsy revealed a necrotic tumor composed of large, atypical cells expressing CD2, CD3, CD43, CD30, CD8 and granzyme B (Fig. 1G). A TCR clone, similar to that observed in the blood sample at initial diagnosis, was identified on the bone biopsy, supporting the diagnosis of LGLL transformation. The patient is awaiting an allogeneic bone marrow transplant.

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Fig. 1: Histological and biological overview of the two clinical cases.
Fig. 2: Molecular whole exome sequencing results and clonal hierarchy hypothesis.

Data availability

The processed somatic mutations and copy number alterations are provided in the Supplementary Datasets. Additional clinical metadata and fastq.gz files are available on request at thierry.lamy@univ-rennes1.fr.

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Acknowledgements

The authors wish to thank the biological resource center (Centre de Ressource Biologique-Santé; Rennes, France BB-0033-0006). This project was funded in part by the Hematology Laboratory at Rennes University Medical Center and the Association pour le Développement de l’Hématologie Oncologie (ADHO).

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Authors and Affiliations

  1. Centre Hospitalier Universitaire de Rennes, Laboratoire d’Hématologie, Rennes, France

    Cédric Pastoret, Marie-Laure Boulland, Mikael Roussel & Thierry Fest

  2. Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche U1236, Université Rennes 1, Rennes, France

    Cédric Pastoret, Roch Houot, Mikael Roussel, Thierry Fest, Thierry Lamy & Tony Marchand

  3. Centre Hospitalier Universitaire de Rennes, Laboratoire d’Anatomopathologie, Rennes, France

    Francisco Llamas-Gutierrez

  4. Centre Hospitalier Universitaire de Rennes, Service de Dermatologie, Rennes, France

    Maxime Fouchard

  5. Centre Hospitalier Universitaire de Rennes, Service d’Hématologie Clinique, Rennes, France

    Aline Moignet, Roch Houot, Thierry Lamy & Tony Marchand

  6. Groupe Hospitalier Henri Mondor, AP-HP, Département de Pathologie, Créteil, France

    Philippe Gaulard

  7. INSERM U955, Institut Mondor de Recherche Biomédicale (IMRB) et Université Paris-Est Créteil, Créteil, France

    Philippe Gaulard

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  1. Cédric Pastoret
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Contributions

CP, TL and TM designed the research and wrote the paper; FLG and PG reviewed the histology data; MF, AM and RH managed the clinical cases; MR provided the flow cytometry data; CP, MLB and TF analyzed the molecular data, all authors critically reviewed the paper.

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Correspondence to Thierry Lamy.

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Pastoret, C., Llamas-Gutierrez, F., Fouchard, M. et al. Molecular mechanisms underlying transformation of large granular lymphocytic leukemia to high-grade T-cell lymphoma. Leukemia 37, 1567–1571 (2023). https://doi.org/10.1038/s41375-023-01922-z

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