STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients.
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.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
Andres
A
Jerez
Michael J
MJ
Clemente
Hideki
H
Makishima
Hanna
H
Rajala
Ines
I
Gómez-Seguí
Thomas
T
Olson
Kathy
K
McGraw
Bartlomiej
B
Przychodzen
Austin
A
Kulasekararaj
Manuel
M
Afable
Holleh D
HD
Husseinzadeh
Naoko
N
Hosono
Francis
F
LeBlanc
Sonja
S
Lagström
Dan
D
Zhang
Pekka
P
Ellonen
André
A
Tichelli
Catherine
C
Nissen
Alan E
AE
Lichtin
Aleksandra
A
Wodnar-Filipowicz
Ghulam J
GJ
Mufti
Alan F
AF
List
Satu
S
Mustjoki
Thomas P
TP
Loughran
Jaroslaw P
JP
Maciejewski
D000328:Adult; D000741:Anemia, Aplastic / Q000150:complications / Q000235:genetics* / Q000401:mortality; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D054066:Leukemia, Large Granular Lymphocytic / Q000150:complications / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics* / Q000401:mortality; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human