Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias.

Abstract

Chronic natural killer large granular lymphocyte (NK-LGL) leukemia, also referred to as chronic lymphoproliferative disorder of NK cells, is a rare disorder defined by prolonged expansion of clonal NK cells. Similar prevalence of STAT3 mutations in chronic T-LGL and NK-LGL leukemia is suggestive of common pathogenesis. We undertook whole-genome sequencing to identify mutations unique to NK-LGL leukemia. The results were analyzed to develop a resequencing panel that was applied to 58 patients. Phosphatidylinositol 3-kinase pathway gene mutations (PIK3CD/PIK3AP1) and TNFAIP3 mutations were seen in 5% and 10% of patients, respectively. TET2 was exceptional in that mutations were present in 16 (28%) of 58 patient samples, with evidence that TET2 mutations can be dominant and exclusive to the NK compartment. Reduced-representation bisulfite sequencing revealed that methylation patterns were significantly altered in TET2 mutant samples. The promoter of TET2 and that of PTPRD, a negative regulator of STAT3, were found to be methylated in additional cohort samples, largely confined to the TET2 mutant group. Mutations in STAT3 were observed in 19 (33%) of 58 patient samples, 7 of which had concurrent TET2 mutations. Thrombocytopenia and resistance to immunosuppressive agents were uniquely observed in those patients with only TET2 mutation (Games-Howell post hoc test, P = .0074; Fisher's exact test, P = .00466). Patients with STAT3 mutation, inclusive of those with TET2 comutation, had lower hematocrit, hemoglobin, and absolute neutrophil count compared with STAT3 wild-type patients (Welch's t test, P ≤ .015). We present the discovery of TET2 mutations in chronic NK-LGL leukemia and evidence that it identifies a unique molecular subtype.

• Authors: Thomas L Olson, HeeJin Cheon, Jeffrey C Xing, Kristine C Olson, Umadevi Paila, Cait E Hamele, Yaseswini Neelamraju, Bryna C Shemo, Matt Schmachtenberg, Shriram K Sundararaman, Mariella F Toro, Cheryl A Keller, Emily A Farber, Suna Onengut-Gumuscu, Francine E Garrett-Bakelman, Ross C Hardison, David J Feith, Aakrosh Ratan, Thomas P Loughran
• Journal: Blood (Blood) Vol. 138 Issue 8 Pg. 662-673 (08 26 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33786584 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• DNA-Binding Proteins
• Neoplasm Proteins
• Dioxygenases
• TET2 protein, human

Topics

• Chronic Disease
• DNA-Binding Proteins (blood, genetics)
• Dioxygenases (blood, genetics)
• Female
• Humans
• Leukemia, Large Granular Lymphocytic (blood, genetics)
• Male
• Mutation
• Neoplasm Proteins (blood, genetics)
• Registries