Large granular lymphocyte (LGL) leukemia is a group of chronic lymphoproliferative disorders of cytotoxic T or natural killer (NK) cells frequently complicated with cytopenia and autoimmune phenomena. 1, 2 In the current World Health Organization (WHO) classification, T-LGL leukemia and chronic lymphoproliferative disorder of NK cells (CLPD-NK) are included in this category. 3 Recurrent somatic mutations in the Src homology 2 (SH2) domain of the signal transducer and activator of transcription 3 (STAT3) gene have been found in T-LGL leukemia and CLPDNK, 4, 5 leading to constitutive activation of STAT3 and dysregulation of genes downstream of STAT3. More recently, mutations outside the SH2 domain have been discovered in T-LGL leukemia. 6 Activating mutations in the SH2 domain of the STAT5B gene were also identified in 2% of LGL leukemia patients, 7 which further underlines the importance of the JAK/STAT signaling pathway in LGL leukemia.

The majority of T-LGL leukemia cases present with a clonal expansion of the CD8 1 LGLs. However, in a small percentage of cases, the tumor cells have a CD4 1 phenotype. 8-10 Cytomegalovirus-derived stimulation and restricted use of the T-cell receptor (TCR)-Vb region has been associated with CD4 1 T-LGL cases, 11 but this rare disease entity still remains poorly described. To further elucidate the pathogenesis of this rare subgroup of T-LGL leukemia, we explored the mutational landscape of CD4 1 cases using exome and targeted amplicon sequencing. Patients diagnosed with T-LGL leukemia and CLPD-NK were recruited. The diagnostic criteria were based on the WHO classifications of 2008. Three patient cohorts (described in