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

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.

• Authors: Nan Jiang, Grace Shimin Koh, Joshua Yew Lim, Shirley Kow Kham, Hany Ariffin, Fook Tim Chew, Allen Eng Yeoh
• Journal: Experimental hematology (Exp Hematol) Vol. 39 Issue 3 Pg. 321-9, 329.e1-3 (Mar 2011) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 21130142 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Hormonal
• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Biomarkers, Tumor
• Membrane Proteins
• Proto-Oncogene Proteins
• Prednisolone

Topics

• Antineoplastic Agents, Hormonal (administration & dosage)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (biosynthesis)
• Bcl-2-Like Protein 11
• Biomarkers, Tumor (biosynthesis)
• Bone Marrow (metabolism)
• Cell Line, Tumor
• Child
• Child, Preschool
• Disease-Free Survival
• Female
• Humans
• Infant
• Male
• Membrane Proteins (biosynthesis)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism, mortality, therapy)
• Prednisolone (administration & dosage)
• Proto-Oncogene Proteins (biosynthesis)
• Survival Rate