Characteristics of the TCR Vβ repertoire in imatinib-resistant chronic myeloid leukemia patients with ABL mutations.

Ling Xu,Yuhong Lu,Xianfeng Zha,Yikai Zhang,Zhenyi Jin,Lijian Yang,Wei Yu,Jing Lai,Yangqiu Li,Yan Xu,Shaohua Chen,Jie Chen

doi:10.1007/s11427-015-4930-4

Abstract

Diversity in the T cell receptor (TCR) repertoire provides a miniature defense ability for the T cell immune system that may be related to tumor initiation and progression. Understanding the T cell immune status of leukemia patients is critical for establishing specific immunotherapies. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vβ T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vβ repertoire in 4 cases with imatinib-resistant CML in blast crisis (BC-CML) with abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase domain mutations (KDMs). Examination of TCR V expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) and GeneScan analysis. Significantly skewed TCR Vβ repertoires were observed in BC-CML patients with different KDMs, and 4 to 8 oligoclonally expanded TCR Vβ subfamilies could be identified in each sample. Intriguingly, a relatively highly expanded Vβ9 clone with the same length as complementarity- determining region 3 (CDR3) (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the only CML patient in myeloid blast crisis (MBC-CML). In conclusion, restricted TCR Vβ repertoire expression and decreased clone complexity was a general phenomenon observed in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency of these patients. In addition, clonally expanded Vβ9 T cell clones may indicate a specific immune response to leukemia-associated antigens in LBC-CML patients.

Highlights

Diversity in the T cell receptor (TCR) repertoire provides a miniature defense ability for the T cell immune system that may be related to tumor initiation and progression
We found that restricted use of the TCR V subfamily is a common characteristic of Chronic myeloid leukemia (CML) patients, and the oligoclonally expanded TCR V 21 subfamily was detected in 27.6% of CML patients and 30.8% of Ph+ B-ALL cases, which may be due to clonal expansion in response to leukemia-associated antigens, such as the BCR-ABL fusion protein [16,17]
We found that the V 9 subfamily was the most frequently clonally expanded TCR family, a clone peak similar to the size of complementarity-determining region 3 (CDR3) (139 bp) could be detected in three of the four samples (P1, patient 2 (P2) and patient 4 (P4)), and the fluorescence intensity captured by the DNA sequenator had a relatively high signal compared with most of the other subfamilies in each sample (Figure 2C)

Summary

Introduction

Diversity in the T cell receptor (TCR) repertoire provides a miniature defense ability for the T cell immune system that may be related to tumor initiation and progression. We found that restricted use of the TCR V subfamily is a common characteristic of CML patients, and the oligoclonally expanded TCR V 21 subfamily was detected in 27.6% of CML patients and 30.8% of Ph+ B-ALL cases, which may be due to clonal expansion in response to leukemia-associated antigens, such as the BCR-ABL fusion protein [16,17] In light of these findings from tyrosine kinase inhibitor (TKI) sensitive CML patients, we investigated whether clonal TCR V restrictions are detectable and whether different characteristics of the TCR V repertoire distribution pattern could be found in IM-resistant BC-CML patients who carry different KDMs

Methods

Results

Conclusion