Familial CD3+ T large granular lymphocyte leukemia: evidence that genetic predisposition and antigen selection promote clonal cytotoxic T-cell responses

Leuk Lymphoma. 2014 Aug;55(8):1781-7. doi: 10.3109/10428194.2013.861065. Epub 2014 Feb 17.


CD3+ T-large granular lymphocyte (T-LGL) proliferations often present with cytopenias and splenomegaly and are linked to autoimmunity, especially rheumatoid arthritis and Felty's syndrome. We report here the intra-family occurrence of T-LGL leukemia in a father and son, both presenting with cytopenias and splenomegaly. Both patients carried the HLA-DRB1*04 allele, strongly associated with rheumatoid arthritis and Felty's syndrome, exhibited distinctive histopathological features suggestive of immune-mediated suppression of hematopoiesis and expressed a remarkably skewed T-cell receptor beta chain gene repertoire with overtime evolution (clonal drift). Immunoinformatics analysis and comparisons with clonotype sequences from various entities revealed (quasi)identities between (i) father and son, and (ii) father or son and patients with autoimmune disorders, T-LGL leukemia or chronic idiopathic neutropenia. Altogether, our results further corroborate antigen selection in the ontogeny of T-LGL leukemia and point to the interplay between genetics and the (micro)environment in shaping the outcome of cytotoxic T cell responses.

Keywords: CDR3; T cell receptor; T-LGL leukemia; T-large granular lymphocyte; antigen; clonal drift.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • CD3 Complex / genetics*
  • CD3 Complex / immunology*
  • CD3 Complex / metabolism
  • Clonal Selection, Antigen-Mediated / genetics
  • Clonal Selection, Antigen-Mediated / immunology
  • Family
  • Genetic Predisposition to Disease
  • Histocompatibility Testing
  • Humans
  • Immunohistochemistry
  • Immunophenotyping
  • Leukemia, Large Granular Lymphocytic / diagnosis
  • Leukemia, Large Granular Lymphocytic / genetics*
  • Leukemia, Large Granular Lymphocytic / immunology*
  • Male
  • Middle Aged
  • Mutation
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Spleen / metabolism
  • Spleen / pathology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism


  • CD3 Complex
  • Receptors, Antigen, T-Cell, alpha-beta
  • STAT3 Transcription Factor