Molecular Analysis of Genes involved in Leukemia
It is now widely accepted that cancer is the result of a multistage process involving the activation of dominant acting oncogenes and the inactivation of tumor suppressor genes. The erytholeukemias induced by Friend virus are amongst the most thoroughly studied experimental models of the multistage nature of cancer. The distinct early and late stages of Friend leukemia, the rapid and efficient induction of disease by a single injection of virus, and the identification of a number of unique host genes that control susceptibility to leukemia induction, provide a unique model for the identification and analysis of genes involved in this multistage malignancy.
The research focus in my laboratory is to understand the molecular mechanisms underlying the multistage malignancy induced by Friend virus. This disease is initiated with a preleukemic and non-tumorigenic stage that is associated with a marked polyclonal increase in the number of erythroid progenitors. The next stage involves the appearance of clonal leukemia cells in the spleens of infected mice. With respect to the genes that are responsible for the transition of polyclonal preleukemic infected erythroid progenitors to clonal leukemic cells, our work and that of others, have shown that the evolution of clonal erytholeukemia by various strains of Friend virus is associated with the inactivation of either of the tumor suppressor genes p53 and p45 NFE2 as well as the activation of either dominant acting oncogenes Fli-1 or Spi-1. The latter two genes encode transcription factors, which belong to the family of ets oncogenes, and are activated as a result of proviral integration in the majority of Friend erytholeukemia cell lines. p53, which is also a transcription factor, is inactivated in the majority of the Friend erytholeukemia cell clones as a result of deletions, proviral insertions and mutations. In addition, we have recently identified another common site for retroviral integration, named Fli-3, from DNA of erytholeukemia cell lines and shown that the coding sequence within this locus is identical to a cluster of microRNA, a new class of gene that is involved in regulation of other genes. Recent studies in my laboratory demonstrated that activation of this gene accelerates the progression of Friend erythroleukemia.
My laboratory is currently investigating the molecular and cellular function of Fli-1, p45 NFE2 and p53. Since Fli-1, p45 NFE2, and p53 are shown to be transcription factors, their function is assumed to regulate the expression of cellular gene(s) that are involved in cell growth and differentiation. Thus, the identity of target genes that their expression are regulated by these proteins may eventually address the broad roles played by these genes in oncogenesis. For example, target genes for Fli-1 have been implicated in erythropoietin signal transduction pathway in erythrocytes. Therefore, study of these genes could increase important insight into normal process of erythropoiesis and malignant transformation. Furthermore we are also studying the possible involvement of Fli-1, Fli-3 and p45 NFE2 in human hematopoietic malignancies.
Graduate Students:
- Mehran Haeri
- Laura Vecchiarelli
Selected References:
Link to Pubmed PublicationsJiu-Wei Cui, You-Jun Li, Aloke Sarkar, Jeremy Brown, Ye-Hui Tan, Marina Premyslova, Crystal Michaud, Norman Iscove, Guan-Jun Wang and Yaacov Ben-David (2007). Retroviral insertional activation of the Fli-3 locus in erythroleukemias encoding a cluster of microRNAs that converts Epo-induced differentiation to proliferation. Blood, 110(7): 2631-40.
Cervi, D., Shaked, Y., Haeri, M., Usenko, T., Lee, C., Hincklin, D., Nagy, A., Kerbel, R.S., Yefenof, E., and Ben-David, Y. (2007). Enhanced Natural Killing and Erythropoietic Activity in VEGF Overexpressing Mice Delays F-MuLV Induced Leukemogenesis. Blood, 109(5):2139-46.
Shaked, Y., Cervi, D., Neuman, M., Pak, B., Kerbel, R.S., and Ben-David, Y. (2005). Splenic microenvironment is a source of angiogenesis/inflammatory mediators accelerating the extramedullary expansion of murine erythroleukemic cells, Blood, 105: 4500-4507.
Truong. A.H.L., Cervi, D., Lee, J., and Ben-David, Y. (2005). Direct transcriptional regulation of MDM2 by Fli-1: A role for Fli-1 in p53 modulation, Oncogene, 24: 962-969.
