CTLA-4 polymorphisms and haplotype correlate with survival in ALL after allogeneic stem cell transplantation from related HLA-haplotype-mismatched donor.
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Disease relapse remains a major cause of transplant failure. T cell homeostasis is critical to determine the potency of the GVT effect. Recent studies have shown the association of the CTLA-4 polymorphisms with the outcome after HLA-identical sibling allogeneic HSCT.


METHODS
In this study, we focused on four CTLA-4 polymorphisms, and analyzed the impact of donor genotypes and haplotypes on the conditions of 152 acute leukemia patients (ALL 83) after related HLA-haplotype- mismatched transplantation. The four SNP genotypes (-1661, -318, CT60 and +49) were determined by TaqMan SNP genotyping assays.


RESULTS
ALL recipients of donors with +49 GG showed significantly lower OS (67.7 vs. 90.3 %, P = 0.015) than those with GA+AA. Multivariate analyses showed that +49 GG was an independent risk factor for OS (HR: 0.306, 95 % CI 0.111-0.842, P = 0.022) .23 ALL patients receiving mDLI showed significantly lower OS with +49 GG donor than those with GA+AA (30.0 vs. 83.1 %, P = 0.003). The haplotype analysis revealed only three haplotypes in the donor population -1661/-318/CT60/+49 i.e., ACGG, ACAA and GTGA, the frequencies were 64.1, 19.4 and 16.5 %, respectively. Donors with and without the ACGG/ACGG haplotype had the same effect on transplant outcomes as those with +49 GG and +49 GA+AA.


CONCLUSIONS
In summary, the CTLA-4 +49 GG and the haplotype ACGG/ACGG reduced the overall survival in ALL after allo-HSCT from the related HLA-haplotype-mismatched donor, knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for donor selection and individual application of immunosuppressive agents and immunotherapy.
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
X-Y
XY
Qin
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
Y
Y
Wang
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
G-X
GX
Li
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
Y-Z
YZ
Qin
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
F-R
FR
Wang
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
L-P
LP
Xu
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
H
H
Chen
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
W
W
Han
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
J-Z
JZ
Wang
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
X-H
XH
Zhang
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
Y-J
YJ
Chang
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
K-Y
KY
Liu
State Key Laboratory of Protein and Plant Gene Research, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education school of Life Sciences, Peking University, Beijing, China.|Peking University-Tsinghua University Joint Center for Life Sciences, Beijing, China.
Z-F
ZF
Jiang
Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China. huangxiaojun@bjmu.edu.cn.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China. huangxiaojun@bjmu.edu.cn.|Peking-Tsinghua Center for Life Sciences, Beijing, China. huangxiaojun@bjmu.edu.cn.|Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking-Tsinghua Center for Life Sciences, 11 Xizhimen South Street, Beijing, 100044, Peoples' Republic of China. huangxiaojun@bjmu.edu.cn.
X-J
XJ
Huang
D000293:Adolescent; D000328:Adult; D060908:CTLA-4 Antigen / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D016019:Survival Analysis; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
D060908:CTLA-4 Antigen
ALL; Allogeneic stem cell transplantation; CTLA-4 polymorphisms; Haplotype; Overall survival