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Prepublished online as a Blood First Edition Paper on June 26, 2003; DOI 10.1182/blood-2003-03-0811.
Submitted March 17, 2003
Accepted June 9, 2003
Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR/ABL and increases sensitivity to STI571
Tim Beissert, Elena Puccetti, Andrea Bianchini, Saskia Guller, Simone Boehrer, Dieter Hoelzer, Oliver G Ottmann, Clara Nervi, and Martin Ruthardt*
Med Klinik III/ Haematologie, J.W. Goethe Universitaet, Frankfurt, Germany
Dipartimento di Istologia ed Embriologia Medica, Universita 'La Sapienza', Roma, Italy
Dipartimento di Istologia ed Embriologia Medica, Universita 'La Sapienza', Roma, Italy; Institute of Cell Biology & Tissue Engineering, San Raffaele Bio-medical Science Park of Rome, Roma, Italy
* Corresponding author; email: ruthardt{at}em.uni-frankfurt.de.
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 complexes (HMW) as compared to 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.
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