Low mRNA expression of the apoptosis-related genes CASP3, CASP8, and FAS is associated with low induction treatment response in childhood acute lymphoblastic leukemia (ALL).
BACKGROUND
Defects in apoptosis signaling have been considered to be responsible for treatment failure in many types of cancer, although with controversial results. The objective of the present study was to assess the expression profile of key apoptosis-related genes in terms of clinical and biological variables and of the survival of children with acute lymphoblastic leukemia (ALL).


METHODS
The levels of mRNA expression of the apoptosis-related genes CASP3, CASP8, CASP9, FAS, and BCL2 were analyzed by quantitative real-time PCR in consecutive samples from 139 consecutive children with ALL at diagnosis treated by the Brazilian protocol (GBTLI-ALL 99). Gene expression levels and clinical and biological features were compared by the Mann-Whitney test. Event-free survival (EFS) was calculated by Kaplan-Meier plots and log-rank test.


RESULTS
A significant correlation was detected between CASP3, CASP8, CASP9, and FAS expression levels (P < 0.01) in ALL samples. Higher levels of BCL2 were significantly associated with white blood cell (WBC) count <50,000/mm(3) at diagnosis (P = 0.01) and low risk group classification (P = 0.008). Lower expression levels of CASP3, CASP8 and FAS gene were associated with a poor response at day 7 according the GBTLI-ALL 99 protocol (P = 0.03, P = 0.02 and P = 0.008, respectively). There was a relationship between FAS gene expression lower than the 75th percentile and lower 5-year EFS (P = 0.02).


CONCLUSIONS
These findings suggest an association between lower expression levels of the pro-apoptotic genes and a poor response to induction therapy at day 7 and prognosis in childhood ALL.
Department Pediatrics, Faculdade de Medicina de Ribeirão Preto-University of São Paulo, Ribeirão Preto, Brazil.
Juliana F
JF
Mata
Vanessa S
VS
Silveira
Elvis C
EC
Mateo
Maria A A
MA
Cortez
Rosane G P
RG
Queiroz
José Andrés
JA
Yunes
Maria Lúcia M
ML
Lee
Sílvia R C
SR
Toledo
Antonio Sérgio
AS
Petrilli
Silvia R
SR
Brandalise
Luiz G
LG
Tone
Carlos A
CA
Scrideli
D000293:Adolescent; D053148:Caspase 3 / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007958:Leukocyte Count; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D015996:Survival Rate; D019014:fas Receptor / Q000235:genetics*
C491901:FAS protein, human; D012333:RNA, Messenger; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8