RNAi-mediated silencing of TEL/AML1 reveals a heat-shock protein- and survivin-dependent mechanism for survival.
The TEL/AML1 fusion gene results from the most frequent t(12;21)(p13;q22) translocation in childhood acute lymphoblastic leukemia (ALL). Its contribution to transformation is largely unknown, in particular with respect to survival and apoptosis. We therefore silenced TEL/AML1 expression in leukemic REH cells by RNA inhibition, which eventually led to programmed cell death. Microarray and 2D gel electrophoresis data demonstrated a differential regulation of heat-shock proteins (HSPs), among them HSP90, as well as of its client, survivin. Consistent with these findings, ectopic expression of TEL/AML1 in Ba/F3 cells increased protein levels of HSP90 and survivin and conferred resistance to apoptotic stimuli. Our data suggest that TEL/AML1 not only contributes to leukemogenesis by affecting an antiapoptotic network but also seems to be indispensable for maintaining the malignant phenotype. The functional relationship between TEL/AML1, HSP90, and survivin provides the rational for targeted therapy, be it the fusion gene or the latter 2 proteins.
Diakos
Christofer
C
Children's Cancer Research Institute (CCRI), Vienna, Austria.
Krapf
Gerd
G
Gerner
Christopher
C
Inthal
Andrea
A
Lemberger
Christof
C
Ban
Jozef
J
Dohnal
Alexander M
AM
Panzer-Grümayer
E Renate
ER
Panzer-Gruemayer
E Renate
ER
D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D000077022:Survivin; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D006360:Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D000077022:Survivin; C107489:BIRC5 protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein