TP53-induced glycolysis and apoptosis regulator protects from spontaneous apoptosis and predicts poor prognosis in chronic lymphocytic leukemia.
Circulating chronic lymphocytic leukemia (CLL) cells appear not to be overly utilizing aerobic glycolysis. However, recurrent contact with CLL cells in a stromal microenvironment leads to increased aerobic glycolysis and the cells' overall glycolytic capacity, which promotes cell survival and proliferation. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been directly implicated in cellular metabolism in the control of glycolysis. TIGAR inhibits glycolysis and protects cells from intracellular reactive oxygen species (ROS)-associated apoptosis.



TIGAR mRNA expression was investigated by quantitative PCR in 102 newly diagnosed CLL patients. Furthermore, the relationship between the expression of TIGAR and its clinical characteristics and prognosis were investigated. Moreover, we also investigated the correlation between TIGAR expression and apoptosis in primary CLL cells.



Our data revealed that TIGAR overexpression was correlated with the protection from spontaneous apoptosis in CLL cells, and is strongly associated with advanced Binet stage, unmutated immunoglobulin heavy-chain variable region (IGHV) status, CD38 positivity, β2-microglobulin and p53 aberrations. Higher expression of TIGAR was associated with shorter treatment-free survival (median: three months vs. 51 months, P=0.0108), worse overall survival (median: 74 months vs. not reached, P=0.0242), and the diverse responses to fludarabine-based chemotherapy. TIGAR expression in patients resistant to chemotherapy was significantly higher than in patients sensitive to chemotherapy (mean: 0.3859±0.1710 vs. 0.0974±0.0291, P=0.0290).



Taken together, our findings revealed that high TIGAR expression is closely correlated with worse clinical outcome in CLL patients, and depicted how bioenergetic characteristics could be therapeutically exploited in CLL.
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Ming
M
Hong
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Yi
Y
Xia
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Yu
Y
Zhu
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Hui-Hui
HH
Zhao
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Han
H
Zhu
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Yue
Y
Xie
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Lei
L
Fan
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Li
L
Wang
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Kou-Rong
KR
Miao
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Hui
H
Yu
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Yu-Qing
YQ
Miao
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Wei
W
Wu
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Hua-Yuan
HY
Zhu
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Yao-Yu
YY
Chen
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Wei
W
Xu
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China. Electronic address: sixuanqiandoc@126.com.
Si-Xuan
SX
Qian
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China; Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, China.
Jian-Yong
JY
Li
D000328:Adult; D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002470:Cell Survival; D005260:Female; D006019:Glycolysis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D055815:Young Adult
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D014740:Vidarabine; C024352:fludarabine
Apoptosis; CLL; Glycolysis; Prognosis; TIGAR