Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR-ABL and increases sensitivity to STI571.
Translocations involving the abl locus on chromosome 9 fuses the tyrosine kinase c-ABL to proteins harboring oligomerization interfaces such as BCR or TEL, enabling these ABL-fusion proteins (X-ABL) to transform cells and to induce leukemia. The ABL kinase activity is blocked by the ABL kinase inhibitor STI571 which abrogates transformation by X-ABL. To investigate the role of oligomerization for the transformation potential of X-ABL and for the sensitivity to STI571, we constructed ABL chimeras with oligomerization interfaces of proteins involved in leukemia-associated translocations such as BCR, TEL, PML, and PLZF. We assessed the capacity of these chimeras to form high molecular weight (HMW) complexes as compared with p185(BCR-ABL). There was a direct relationship between the size of HMW complexes formed by these chimeras and their capacity to induce factor independence in Ba/F3 cells, whereas there was an inverse relationship between the size of the HMW complexes and the sensitivity to STI571. The targeting of the oligomerization interface of p185(BCR-ABL) by a peptide representing the coiled coil region of BCR reduced its potential to transform fibroblasts and increased sensitivity to STI571. Our results indicate that targeting of the oligomerization interfaces of the X-ABL enhances the effects of STI571 in the treatment of leukemia caused by X-ABL.
Beissert
Tim
T
Med. Klinik III/Abtl. Hämatologie, Klinikum der J.W. Goethe Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany.
Puccetti
Elena
E
Bianchini
Andrea
A
Güller
Saskia
S
Boehrer
Simone
S
Hoelzer
Dieter
D
Ottmann
Oliver Gerhard
OG
Nervi
Clara
C
Ruthardt
Martin
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D018076:DNA, Complementary / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry*; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D018076:DNA, Complementary; D015513:Oncogene Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr