SLUG in cancer development

The SNAIL-related zinc-finger transcription factor, SLUG (SNAI2), is critical for the normal development of neural crest-derived cells and loss-of-function SLUG mutations have been proven to contribute to piebaldism and Waardenburg syndrome type 2 in a dose-dependent fashion. While aberrant induction of SLUG has been documented in cancer cells, relatively little is known about the consequences of SLUG overexpression in malignancy. To investigate the potential role of SLUG overexpression in development and in cancer, we generated mice carrying a tetracycline-repressible Slug transgene. These mice were morphologically normal at birth, and developed mesenchymal tumours (leukaemia and sarcomas) in almost all cases examined. Suppression of the Slug transgene did not rescue the malignant phenotype. Furthermore, the BCR–ABL oncogene, which induces Slug expression in leukaemic cells, did not induce leukaemia in Slug-deficient mice, implicating Slug in BCR–ABL leukaemogenesis in vivo. Overall, the findings indicate that while Slug overexpression is not sufficient to cause overt morphogenetic defects in mice, they demonstrate a specific and critical role for Slug in the pathogenesis of mesenchymal tumours.Research in our group is supported by MEyC (BIO2000-0453-P4-02, SAF2003- 01103and FIT-010000-2004-157), Junta de Castilla y León (CSI06/03), ADE de Castilla y León (04/04/SA/0001), FIS (PI020138, G03/179, and G03/136) and USALCIBASA project. MPC is a recipient of an MCyT fellowship and MSM is supported by Fundación Cientíica de la AECC.Peer reviewe

Philadelphia-positive B-cell acute lymphoblastic leukemia is initiated in an uncommitted progenitor cell

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the c-ABLgene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABLp190 and BCR-ABLp210, are produced that are characteristic of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (Ph1-ALL) respectively. In CML, it is evident that the transformation occurs at the level of pluripotent stem cells. However, Ph1-ALL has been thought to affect progenitor cells with lymphoid differentiation. Recently, it has been demonstrated that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph1-ALL. In this review, we discuss what is known about the relationship between the specific BCR-ABLp190 oncogene, the target cell and the characteristics of the subsequent disease process it causes. We also discuss how this information may be applied to the establishment of new directions in therapy.Peer Reviewe

Characterization of p87C3G, a novel, truncated C3G isoform that is overexpressed in chronic myeloid leukemia and interacts with Bcr-Abl

A novel C3G isoform, designated p87C3G, lacking the most amino terminal region of the cognate protein has been found to be overexpressed in two CML cell lines, K562 and Boff 210, both expressing Bcr-Abl p210. p87C3G expression is also highly augmented in patients diagnosed with chronic myeloid leukemia (CML) Ph+, in comparison with healthy individuals, and returns to basal levels after treatment with STI571. p87C3G coimmunoprecipitates with both CrkL and Bcr-Abl in CML cell lines and coimmunoprecipitation between p87C3G and Bcr-Abl was also detected in primary cells from CML patients. These interactions have been confirmed by in vitro pull down experiments. The interaction between p87C3G and Bcr-Abl involves the SH3-binding domain of p87C3G and the SH3 domain of Abl and depends mostly on the first polyproline region of p87C3G. Furthermore, we also demonstrated that p87C3G is phosphorylated in vitro by a Bcr-Abl-dependent mechanism. These results indicate that p87C3G overexpression is linked to CML phenotype and that p87C3G may exert productive functional interactions with Bcr-Abl signaling components suggesting the implication of this C3G isoform in the pathogenesis of chronic myeloid leukemia. © 2005 Elsevier Inc. All rights reserved.This work was supported by grants SA17/02 and SA013/02 from Junta de Castilla y León, SAF2003-04177 and GEN2003- 20239-C06-02 from the Spanish Ministry of Education, FISFEDER PI021570 and FIS-FEDER PI030651 from the Spanish Ministry of Health. J.G., E.C. and S.M.-E. are predoctoral fellows supported by the Spanish Ministry of Education. J.M.H. was supported by a Biomedicine Research Grant from Sacyl, Junta de Castilla y Leon, Spain. C.G. was supported by the Ramón y Cajal Program from the Spanish Ministry of Education.Peer Reviewe

Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice

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.Peer reviewe

Selective destruction of tumor cells through specific inhibition of products resulting from chromosomal translocations

A key problem in the effective treatment of patients with cancer (both leukemia and solid tumors) is to distinguish between tumor and normal cells. This problem is the main reason why current treatments for cancer are often ineffective. There have been remarkable advances in our understanding of the molecular biology of cancer that provides new selective tumor destruction mechanisms. The molecular characterization of the tumor-specific chromosomal abnormalities has revealed that fusion proteins are the consequence in the majority of cancers. These fusion proteins result from chimeric genes created by the translocations, which form chimeric mRNA species that contain exons from the genes involved in the translocation. Obviously, these chimeric molecules are attractive therapeutic targets since they are unique to the disease (they only exist in the tumor cells but not in the normal cells of the patient), allowing the design of specific anti-tumor drugs. Inhibition of chimeric gene expression by anti-tumor agents specifically kills leukemic cells without affecting normal cells. As therapeutic agents targeting chimeric genes, zinc-finger proteins, antisense RNAs or hammerhead-based ribozymes have been used. All of these agents have some limitations, indicating that new therapeutic tools are required as gene inactivating agents that should be able to inhibit any chimeric fusion gene product. Recently, we have used the catalytic RNA subunit of RNase P from Escherichia coli, which can be specifically directed to cut any mRNA sequence, to specifically destroy tumor-specific fusion genes created as a result of chromosomal translocations. In this chapter, we will review the advances made to selectively destroy tumor cells through specific inhibition of products resulting from chromosomal translocations.Peer reviewe