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.

journal_name

Oncogene

journal_title

Oncogene

authors

Pérez-Caro M,Gutierrez-Cianca N,González-Herrero I,López-Hernández I,Flores T,Orfao A,Sánchez-Martín M,Gutiérrez-Adán A,Pintado B,Sánchez-García I

doi

10.1038/sj.onc.1209968

subject

Has Abstract

pub_date

2007-03-15 00:00:00

pages

1702-13

issue

12

eissn

0950-9232

issn

1476-5594

pii

1209968

journal_volume

26

pub_type

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