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01.12.2013 | Letter to the Editor | Ausgabe 1/2013 Open Access

Journal of Hematology & Oncology 1/2013

STAT3 mutations are frequent in T-cell large granular lymphocytic leukemia with pure red cell aplasia

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2013
Autoren:
Zhi-Yuan Qiu, Lei Fan, Li Wang, Chun Qiao, Yu-Jie Wu, Jian-Feng Zhou, Wei Xu, Jian-Yong Li
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1756-8722-6-82) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

ZYQ performed the laboratory work for this study and wrote the manuscript; LF and LW provided material and clinical information; CQ and YJW designed the experiments; JFZ analyzed data; WX and JYL performed statistical analysis and wrote the manuscript. All authors have approved the final version of the manuscript.
Abbreviations
T-LGLL
T-cell large granular lymphocytic leukemia
STAT3
Signal transducer and activator of transcription 3
PRCA
Pure red blood cell aplasia
LDH
Lactic dehydrogenase
β2-MG
β2-microglobulin
TFS
Treatment-free survival
PB
Peripheral blood
ANC
Absolute neutrophil count
RA
Rheumatoid arthritis.

To the editor

T-cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder and can cooccur in the context of pure red cell aplasia (PRCA) [13]. Recently, recurrent somatic mutations in the Src homology domain of the signal transducer and activator of transcription 3 (STAT3) gene have been identified to have a high frequency of 40% [4] and 33% [5] in T-LGLL. To analyze the STAT3 mutation status and its clinical significance, we investigated STAT3 mutations in 28 consecutive patients with newly diagnosed T-LGLL who were recruited between January 2007 and January 2013. The diagnosis of T-LGLL was based on the WHO criteria [1]. The diagnosis of PRCA was defined according to the previous report [6].

Findings

For STAT3 mutation screening, genes of exons 20 and 21 of STAT3 were amplified by PCR and sequenced. Five different mutations (Y640F, D661Y, E616V, V671F, S614R) were observed, and two mutations, E616V and V671F, had not been previously reported. STAT3 is an oncogene, and its activation plays a key role in cell signaling in many types of cancer [7]. In our study, all mutations were heterozygous and the mutational hot spot were located close to the transcriptional activation domain.
Seven patients (25%) were found to have both T-LGLL and PRCA. STAT3 mutation was more common among patients with PRCA than those without PRCA (71.4% vs.4.8%, P = 0.001). Six of 7 (85.7%) patients with PRCA were found to have elevated β2-MG (β2-microglobulin), which was significantly higher than was found in 6 of 18 (33.3%) patients without PRCA (P = 0.030, Table 1). On the other hand, patients with STAT3 mutations had presented with neutropenia more often than those without STAT3 mutations (100% vs. 40.9%, P = 0.018), and this is similar to previous studies [4].
Table 1
Comparison of clinical characteristics between T-LGLL patients with or without PRCA
 
Patients with PRCA (7)
Patients without PRCA (21)
P
Gender
  
1.000
Male
3 (42.9)
8 (38.1)
 
Female
4 (57.1)
13 (61.9)
 
Age
  
0.668
  Mean ± SD
57.3 ± 10.2
55.4 ± 9.0
 
LDH
  
0.165
  >250 U/L
4 (57.1)
5 (23.8)
 
  <250 U/L
3 (42.9)
16 (76.2)
 
β2-MG (n = 25)
  
0.030
  >3.0 mg/L
6 (85.7)
6 (33.3)
 
  <3.0 mg/L
1 (14.3)
12 (66.7)
 
Neutropenia, no.%
6 (85.7)
9 (42.9)
0.084
Lymphocytosis, no.%
4 (57.1)
11 (52.4)
1.000
LGL count in PB,×109/L
  
0.295
  Mean ± SD
3.2 ± 2.1
2.9 ± 1.7
 
Splenomegaly, no.%
5 (71.4)
5 (23.8)
0.063
STAT3 mutation
5 (71.4)
1 (4.8)
0.001
PB: peripheral blood; STAT3: signal transducer and activator of transcription 3; Anemia:hemoglobin (Hb) <100 g/L; Neutropenia: absolute neutrophil count (ANC) <1.5 × 109/L.
LDH: lactic dehydrogenase.
Anemia, neutropenia and rheumatoid arthritis (RA) are common complications, and anemia is more common in Asian countries [8, 9]; neutropenia and RA is more common in Western countries [10, 11], but there was no patients with RA in our study. We show here that the coexistence of PRCA or neutropenia is more frequent in patients with STAT3 mutation. This observation varies from from the study of Jerez et al. [5] and Koskela et al. [4], but is consistent with the study from Japan [12].
TFS was defined as the period from the diagnosis date to the time of the first treatment. In our study, we observed a significant difference between patients with or without STAT3 mutations in TFS (median 6.5 months vs. 16.6 months, P = 0.008, Figure 1A), and we observed a significant difference between the high β2-MG group and the low β2-MG group in TFS (P = 0.003 Figure 1C). TFS was not related to LDH levels (Figure 1B).
To our knowledge, our study is the first report on STAT3 mutation status in patients with T-LGLL in China. Although the STAT3 mutation thus likely contributes to the pathogenesis of T-LGLL, patients without STAT3 mutations are characterized by significant heterogeneity, indicating that other mechanisms of STAT3 activation can be operative in this disease. Further studies are therefore necessary to determine other reasons to lead to the pathogenesis of T-LGLL.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant Nos. 30871104, 30971296, 81170485, 81170488), the Natural Science Foundation of Jiangsu Province (Grant No. BK2010584), Key Projects of Health Department of Jiangsu Province (Grant No. K201108), Jiangsu Province’s Medical Elite Program (Grant No. RC2011169), National Public Health Grand Research Foundation (No.201202017) , Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institute (No. JX10231801), the Program for Development of Innovative Research Teams in the First Affiliated Hospital of Nanjing Medical University, and Project of National Key Clinical Specialty.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

ZYQ performed the laboratory work for this study and wrote the manuscript; LF and LW provided material and clinical information; CQ and YJW designed the experiments; JFZ analyzed data; WX and JYL performed statistical analysis and wrote the manuscript. All authors have approved the final version of the manuscript.

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