Large granular lymphocyte (LGL) leukemia is a category of uncommon lymphoproliferative illnesses with an unknown molecular landscape. For a study, researchers used paired whole-exome and transcriptome sequencing to study the largest LGL leukemia cohort, which included 105 patients (93 T-cell receptor αβ [TCRαβ] T-LGL and 12 TCRγδ T-LGL). 

About 76 variants were found in three or more individuals in the group, including STAT3, KMT2D, PIK3R1, TTN, EYS, and SULF1 mutations shared by both subtypes. In addition, using an unbiased driver analysis technique and whole-exome cohort, they found ARHGAP25, ABCC9, PCDHA11, SULF1, SLC6A15, DDX59, DNMT3A, FAS, KDM6A, KMT2D, PIK3R1, STAT3, STAT5B, TET2, and TNFAIP3 as recurrently mutated putative drivers. 

There were hotspot mutations in STAT3, PIK3R1, and FAS, as well as truncating mutations in epigenetic modifying enzymes such as KMT2D and TET2. Furthermore, STAT3 mutations were associated with chromatin and epigenetic modifying gene alterations, particularly KMT2D and SETD1B (P<.01 and P<.05, respectively). In 50.5% of the patients, STAT3 was mutated. The most prevalent STAT3 mutation, Y640F, was linked to lower absolute neutrophil count values, whereas the N647I mutation was linked to lower hemoglobin levels. In addition, the STAT3 coiled-coil domain was studied for somatic activating mutations (Q160P, D170Y, L287F). STAT3 mutation patients had a higher mutational load and were more likely to have a mutational profile associated with enhanced spontaneous deamination of 5-methylcytosine. Finally, gene expression analysis indicated that STAT3-mutant patients had increased interferon signaling and reduced phosphatidylinositol 3-kinase–Akt signaling.