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


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.
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.
Nan
N
Jiang
Grace Shimin
GS
Koh
Joshua Yew
JY
Lim
Shirley Kow
SK
Kham
Hany
H
Ariffin
Fook Tim
FT
Chew
Allen Eng
AE
Yeoh
D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D011239:Prednisolone / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D015996:Survival Rate
D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011239:Prednisolone