Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome.
We have found that, in addition to Bcl-2 and Bax, the expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-xL, Mcl-1) were highly variable in blasts from 78 children with newly diagnosed acute lymphoblastic leukemia (ALL). The patients were enrolled in the national study ALL-7 of the Dutch Childhood Leukemia Study Group. In contrast to Bcl-2 that inversely correlated with %S-phase cells and WBC, and was lower in T than in B-lineage ALL, the Bcl-2 family members were not found to be associated with features at presentation. These expression levels were also compared with drug resistance in in vitro MTT (methyl-thiazol-tetrazolium) assays for prednisolone, vincristine and asparaginase in 46 children. Protein expression levels of the Bcl-2 family were not found to correlate with in vitroresistance to the individual drugs or the combined drug resistance profile. In addition, neither peripheral blast reduction after 1 week of prednisone monotherapy nor long-term disease-free interval or survival showed a correlation with protein expression. Our results indicate that the anti-proliferative function of Bcl-2 dominates its anti-apoptotic function in ALL, but neither Bcl-2 nor the Bcl-2 family members gained prognostic information in the risk-adapted protocol ALL-7.
Salomons
G S
GS
Divisions of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands.
Smets
L A
LA
Verwijs-Janssen
M
M
Hart
A A
AA
Haarman
E G
EG
Kaspers
G J
GJ
Wering
E V
EV
Der Does-Van Den Berg
A V
AV
Kamps
W A
WA
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D019254:Genes, bcl-2; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D005810:Multigene Family; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured