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Exp Hematol. 2011 Mar;39(3):321-9, 329.e1-3. doi: 10.1016/j.exphem.2010.11.009. Epub 2010 Dec 2.

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

Author information

1
Department of Paediatrics, Division of Haematology and Oncology,Yong Loo Lin School of Medicine, National University Hospital, National University of Singapore, 5 Lower Kent Ridge Road, Singapore.

Abstract

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.

PMID:
21130142
DOI:
10.1016/j.exphem.2010.11.009
[Indexed for MEDLINE]

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