STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients

Abstract

Large granular lymphocyte leukemia (LGL) is often associated with immune cytopenias and can cooccur in the context of aplastic anemia (AA) and myelodysplastic syndromes (MDS). We took advantage of the recent description of signal transducer and activator of transcription 3 (STAT3) mutations in LGL clonal expansions to test, using sensitive methods, for the presence of these mutations in a large cohort of 367 MDS and 140 AA cases. STAT3 clones can be found not only in known LGL concomitant cases, but in a small proportion of unsuspected ones (7% AA and 2.5% MDS). In STAT3-mutated AA patients, an interesting trend toward better responses of immunosuppressive therapy and an association with the presence of human leukocyte antigen-DR15 were found. MDSs harboring a STAT3 mutant clone showed a lower degree of bone marrow cellularity and a higher frequency of developing chromosome 7 abnormalities. STAT3-mutant LGL clones may facilitate a persistently dysregulated autoimmune activation, responsible for the primary induction of bone marrow failure in a subset of AA and MDS patients.

Figure 1

Study flow diagram and frequency of confirmed STAT3-mutated patients. (A) Screening-confirmation pipeline. Several sequencing methods with increasing sensitivity were used to confirm the ARMS-PCR–positive cases. (B) Venn diagram showing the clinically detected overlapping of LGL with AA and MDS, and an additional percentage of STAT3⁺, clinically unsuspected concomitant LGL/BMF.

Figure 2

D661Y STAT3 mutation in a hypocellular MDS case. (A-B) Immunodominant Vβ1 fraction before sorting; among the CD8 Vβ repertoire; and blood mononuclear cells. (C-D) Vβ1-positive and -negative fraction after blood mononuclear cell sorting. (E) Presence of the ARMS-PCR D661Y allele only in the Vβ1⁺ population.

Figure 3

Differences in survival outcomes in acquired BMF patients according to the presence of a STAT3 mutated clone. (A-B) No difference is seen in survival when comparing AA and MDS patients with or without the STAT3-mutated CTL clone.