BIM is a prognostic biomarker for early prednisolone response in pediatric acute lymphoblastic leukemia

被引:32
|
作者
Jiang, Nan [1 ]
Koh, Grace Shimin [1 ]
Lim, Joshua Yew Suang [1 ]
Kham, Shirley Kow Yin [1 ]
Ariffin, Hany [2 ]
Chew, Fook Tim [3 ]
Yeoh, Allen Eng Juh [4 ,5 ,6 ]
机构
[1] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Paediat, Singapore 117595, Singapore
[2] Univ Malaya, Dept Paediat, Kuala Lumpur, Malaysia
[3] Natl Univ Singapore, Dept Biol Sci, Lee Hiok Knee Funct Genom Labs, Allergy & Mol Immunol Lab,Fac Sci, Singapore 117548, Singapore
[4] Natl Univ Hlth Syst, Natl Univ Hosp, Yong Loo Lin Sch Med, Dept Paediat,Div Haematol & Oncol, Singapore 119074, Singapore
[5] Natl Univ Hlth Syst, Univ Childrens Med Inst, Viva Univ Childrens Canc Ctr, Singapore 119074, Singapore
[6] Natl Univ Hlth Syst, Natl Univ Canc Inst, Singapore 119074, Singapore
关键词
GLUCOCORTICOID-INDUCED APOPTOSIS; BH3-ONLY PROTEIN BIM; ONCOLOGY-GROUP; CELLS; INDUCTION; FAMILY; ACTIVATION; EXPRESSION; INHIBITORS; MODELS;
D O I
10.1016/j.exphem.2010.11.009
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. Glucocorticoids such as prednisolone (PRED) are widely used in the treatment of pediatric acute lymphoblastic leukemia. In PRED-induced apoptosis, Bcl-2 family members play important regulatory roles. However, the exact members involved remain unknown. In this study, the roles of Bcl-2 family members in PRED-induced apoptosis and their prognostic value to day 8 PRED response are evaluated. Materials and Methods. Four clinically important acute lymphoblastic leukemia cell lines, three PRED-sensitive (697, Sup-B15, and RS4;11) and one PRED-resistant (REH) were studied. Thirty paired patient bone marrow samples were obtained at diagnosis (day 0) and after 7 days (day 8) of PRED monotherapy: Twenty-five patients had PRED good response and five PRED poor response. Differential expressions of Bcl-2 members were observed in those samples and BIM was further investigated using gene silencing technology in representative cell line Sup-B15. Results. The proapoptotic BH3-only Bcl-2 family member BIM was upregulated only in PRED-sensitive cells. Receiver operating characteristic curve analysis showed that BIM expression was highly predictive of PRED response (area under the curve = 0.81; p = 0.032) in paired patient bone marrow samples and is, most excitingly, independent of molecular subtype. Patients whose BIM protein expression levels fail to upregulate at day 8 compared to day 0 (D8/D0 ratio <0.93) have significantly poorer event-free survival (60%) than those patients whose BIM protein expression levels did upregulate (92%). By silencing BIM in PRED-sensitive cells, PRED-induced apoptosis was inhibited. Conclusions. Upregulation of BIM by PRED in acute lymphoblastic leukemia cells regardless of molecular subtype is significantly prognostic of outcomes, confirming BIM's essential regulatory role in the PRED-induced apoptosis. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
引用
收藏
页码:321 / 329
页数:9
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