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Cited by 65

The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.

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

Olson, Thomas L., Cheon, HeeJin, Xing, Jeffrey C., Olson, Kristine C., Paila, Umadevi, Hamele, Cait E., Neelamraju, Yaseswini, Shemo, Bryna C., Schmachtenberg, Matt, Sundararaman, Shriram K., Toro, Mariella F., Keller, Cheryl A., Farber, Emily A., Onengut-Gumuscu, Suna, Garrett-Bakelman, Francine E., Hardison, Ross C., Feith, David J., Ratan, Aakrosh, Loughran, Thomas P.·2021·Blood
DOI 10.1182/blood.2020005831
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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.

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Metadata

Authors
Olson, T. L., Cheon, H., Xing, J. C., Olson, K. C., Paila, U., Hamele, C. E., Neelamraju, Y., Shemo, B. C., Schmachtenberg, M., Sundararaman, S. K., Toro, M. F., Keller, C. A., Farber, E. A., Onengut-Gumuscu, S., Garrett-Bakelman, F. E., Hardison, R. C., Feith, D. J., Ratan, A., & Loughran, T. P.
Affiliations
  • University of Virginia Cancer Center, Charlottesville, VA;
  • Center for Public Health Genomics, University of Virginia, Charlottesville; VA;
  • Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA;
  • Department of Biochemistry and Molecular Biology, Center for Computational Biology & Bioinformatics, The Pennsylvania State University, State College, PA; and
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-03-30
Volume
138
Issue
8
Pages
662-673
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood.2020005831
Cited by
65
References
57
Language
en

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