title: Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice.
abstract: Pharmacological inactivation of cancer genes or products is being used as a strategy for therapy in oncology. To investigate the potential role of BCR-ABLp190 cessation in leukaemia development, we generated mice carrying a tetracycline-repressible BCR-ABLp190 transgene. These mice were morphologically normal at birth, and developed leukaemias. Disease was characterized by the presence of B-cell blasts co-expressing myeloid markers, reminiscent of the human counterpart. BCR-ABLp190 activation can initiate leukaemia in both young and adult mice. Transitory expression of BCR-ABLp190 is enough to develop leukaemia. Suppression of the BCR-ABLp190 transgene in leukaemic CombitTA-p190 mice did not rescue the malignant phenotype, indicating that BCR-ABLp190 is not required to maintain the disease in mice. Similar results were obtained by inactivation of BCR-ABLp190 with STI571 (Gleevec; Novartis, East Hanover, NJ, USA) in leukaemic CombitTA-p190 mice. However, gradual suppression of BCR-ABLp190 in leukaemic CombitTA-p190 mice identified a minimum level of BCR-ABLp190 expression necessary to revert the specific block in B-cell differentiation in the leukaemic cells. Overall, the findings indicate that BCR-ABLp190 appears to cause epigenetic and/or genetic changes in tumour-maintaining cells that render them insensitive to BCR-ABLp190 inactivation.
authors.affiliation: Laboratorio 13, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus Unamuno, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pérez-Caro
authors.forename: N
authors.initials: N
authors.lastname: Gutierrez-Cianca
authors.forename: I
authors.initials: I
authors.lastname: González-Herrero
authors.forename: I
authors.initials: I
authors.lastname: López-Hernández
authors.forename: T
authors.initials: T
authors.lastname: Flores
authors.forename: A
authors.initials: A
authors.lastname: Orfao
authors.forename: M
authors.initials: M
authors.lastname: Sánchez-Martín
authors.forename: A
authors.initials: A
authors.lastname: Gutiérrez-Adán
authors.forename: B
authors.initials: B
authors.lastname: Pintado
authors.forename: I
authors.initials: I
authors.lastname: Sánchez-García
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D020868:Gene Silencing; D007942:Leukemia, Experimental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
chemical_list: D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl