<i>STAT3</i> and <i>STAT5B </i>Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features

• Main Authors: Noemí Muñoz-García, María Jara-Acevedo, Carolina Caldas, Paloma Bárcena, Antonio López, Noemí Puig, Miguel Alcoceba, Paula Fernández, Neus Villamor, Juan A. Flores-Montero, Karoll Gómez, María Angelina Lemes, Jose Carlos Hernández, Iván Álvarez-Twose, Jose Luis Guerra, Marcos González, Alberto Orfao, Julia Almeida
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Cancers
• Subjects: large granular lymphocytic leukemia; <i>STAT3 </i>and <i>STAT5B</i> mutations; T and NK cells; neutropenia; normal leukocyte subsets
• Online Access: https://www.mdpi.com/2072-6694/12/12/3508
• ISSN: 2072-6694

<i>STAT3</i> and <i>STAT5B </i>(<i>STAT3/STAT5B</i>) mutations are the most common mutations in T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK), but their clinical impact remains unknown. We investigated the frequency and type of <i>STAT3/STAT5B</i> mutations in FACS-sorted populations of expanded T/NK-LGL from 100 (82 clonal; 6 oligoclonal; 12 polyclonal) patients, and its relationship with disease features. Seventeen non-LGL T-CLPD patients and 628 age-matched healthy donors were analyzed as controls. <i>STAT3 </i>(<i>n</i> = 30) and <i>STAT5B </i>(<i>n</i> = 1) mutations were detected in 28/82 clonal T/NK-LGLL patients (34%), while absent (0/18, 0%) among oligoclonal/polyclonal LGL-lymphocytosis. Mutations were found across all diagnostic subgroups: TCD8⁺-LGLL, 36%; CLPD-NK, 38%; TCD4⁺-LGLL, 7%; Tαβ⁺DP-LGLL, 100%; Tαβ⁺DN-LGLL, 50%; Tγδ⁺-LGLL, 44%. <i>STAT3</i>-mutated T-LGLL/CLPD-NK showed overall reduced (<i>p</i> < 0.05) blood counts of most normal leukocyte subsets, with a higher rate (vs. nonmutated LGLL) of neutropenia (<i>p</i> = 0.04), severe neutropenia (<i>p</i> = 0.02), and cases requiring treatment (<i>p</i> = 0.0001), together with a shorter time-to-therapy (<i>p</i> = 0.0001), particularly in non-Y640F <i>STAT3-</i>mutated patients. These findings confirm and extend on previous observations about the high prevalence of <i>STAT3</i> mutations across different subtypes of LGLL, and its association with a more marked decrease of all major blood-cell subsets and a shortened time-to-therapy.