Frequently ABL kinase domain G:C→A:T mutation and uracil DNA glycosylase abnormal expression in TKI-resistant acute lymphoblastic leukemia of Chinese population.
10.7534/j.issn.1009-2137.2014.04.002
- Author:
Hong-Jie SHEN
1
;
Zi-Xing CHEN
2
;
Jun HE
1
;
Jian-Nong CEN
1
;
Qiao-Chen QIU
1
;
Zi-Xuan DING
1
;
Li YAO
1
;
Yan CHEN
1
;
Su-Ning CHEN
1
;
Yong-Quan XUE
1
Author Information
1. Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Jiangsu Insitute of Hematology, The First Affiliate Hospital of Soochow University, Suzhou 215006, Jiansu Province, China.
2. Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Jiangsu Insitute of Hematology, The First Affiliate Hospital of Soochow University, Suzhou 215006, Jiansu Province, China. E-mail: szchenzx@263.net.
- Publication Type:Journal Article
- MeSH:
Adolescent;
Adult;
Asian Continental Ancestry Group;
genetics;
DNA Glycosylases;
genetics;
Drug Resistance, Neoplasm;
genetics;
Female;
Humans;
Male;
Middle Aged;
Point Mutation;
Precursor Cell Lymphoblastic Leukemia-Lymphoma;
genetics;
Protein Kinase Inhibitors;
pharmacology;
Uracil-DNA Glycosidase;
genetics
- From:
Journal of Experimental Hematology
2014;22(4):889-893
- CountryChina
- Language:Chinese
-
Abstract:
Most Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) patients often show rapid recurrence and development of ABL kinase domain (KD) mutation after tyrosine kinase inhibitor (TKI) treatment. To further investigate the mechanism of Ph(+) ALL fast relapse after TKI treatment, ABL KD mutation in 35 Chinese Ph(+) ALL with TKI resistance was detected by direct sequencing. The results showed that 77.1% (27/35) Ph(+) ALL patients with TKI resistance had ABL KD mutation and 55.6% (15/27) Ph(+) ALL patients with ABL KD mutation had T315I. Interestingly, 77.8% (21/27) Ph(+)ALL showed ABL mutation G: C→A:T, including T315I, E255K and E459K. Furthermore, all the Ph(+) ALL patients with two or more ABL KD mutations collaborated with complex chromosome abnormality and all the TKI-resistant Ph(+) ALL patients, whose karyotype progressed from simple t (9;22) into complex, developed ABL KD mutation. Moreover, the expression level of uracil-DNA glycosylase UNG2, which inhibits G:C→A:T transition in genomic DNA, decreased in Ph(+) ALL with TKI-resistance compared to that in newly diagnosis Ph(+) ALL. It is concluded that there is a high frequent ABL KD G:C→A:T mutation and a high genomic instability in Chinese TKI-resistant Ph(+) ALL. In addition, the decreased UNG2 expression in TKI-resistant Ph(+) ALL probably contributes to their high rate of ABL KD G:C→A:T mutation.
