Assistant Professor of Oncology
Department of Cancer Genetics

Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
Telephone: (716)845-8821
Fax: (716)845-1698
E-mail: Yurij.Ionov@RoswellPark.org

General Research Interest

To study molecular pathways leading to malignant transformation of cells using a genetic approach.

Current Program

• Identification of novel tumor suppressor genes related to colon cancer. Identification of novel tumor suppressor genes related to prostate cancer.
• Identification of pathways leading to malignant transformation of breast epithelial cells.

Laboratory Personnel

Dimiter Kunnev PhD
Olga Leontieva PhD

Description of Research

Cancer is a complex genetic disease which occurs due to malfunctioning of several genetic pathways controlling the balance between cell replication and cell death. Many oncogenes and tumor suppressor genes that constitute cancer pathways are still unknown. The focus of our lab is to identify of novel tumor suppressor genes and delineate pathways that lead to cell transformation.

Many tumor suppressor genes frequently contain inactivating frameshift or nonsense mutations in cancer cells. Such mutations, if they occur more than 25 bp upstream of the last exon/exon junction lead to a rapid degradation of the mutant mRNA through the NMD pathway. Inhibition of NMD results in the increase of mutant mRNA that can be detected using microarray analysis. We use inhibition of NMD in cancer cell lines and microarray analysis to identify genes that contain nonsense or frameshift mutations.

We use cancer cell lines with microsatellite instability (that is with inactivated DNA mismatch repair (MMR)) as a tool to identify novel tumor suppressor genes, since in cells with inactive MMR tumor suppressor genes most probably are inactivated by nonsense or frameshift mutations that can be identified using inhibition of NMD approach. We have identified a number of genes that contain inactivating mutation in both alleles in prostate and colon cancer cell lines with microsatellite instability. Molecular and cellular biology approaches are being used to analyze these genes further to define their role in cancer development. Genes that contain biallelic inactivating mutations in cell lines with microsatellite instability are not necessary mutated in tumors with functional mismatch repair. However these genes will pinpoint the pathways that may be inactivated. Other genes of the same pathway can be mutated or downregulated by other mechanisms in such tumors. Therefore, identifying mutant genes in colon and/or prostate cancer cell lines and proving their tumor suppressor capabilities using functional studies will help to delineate the pathways that lead to malignant transformation.

The progression events associated with tumor development and metastasis results from the acquisition of mutational events in key cancer related genes. In an attempt to identify these events we are also using an in vitro random frameshift mutagenesis approach to generate transformed clones from non-transformed but immortalized breast epithelial cells. We will use inhibition of NMD to analyze these clones to identify genes that contain de novo frameshift mutations. These genes will also be analyzed for the presence of mutations, or loss of expression, in primary tumors which will identify them as tumor suppressor genes.

Key Publications

• Ivanov I, Lo KC, Hawthorn L, Cowell JK, Ionov Y.  Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediate mRNA decay in colon cancer cells. 2007; 26(20)2873-2884.
• Rossi MR, Ionov Y, Bakin AV, Cowell JK. Truncating mutations in the ACVR2 gene attenuates activin signaling in prostate cancer cells. Cancer Genet Cytogenet 2005; 162:123-129.
• Rossi MR, Hawthorn L, Platt J, Burkhardt, T, Cowell JK, Ionov Y. Identification of inactivating mutations of the JAK1 SYNJ2 and CLPTMl gene in cancer cells using inhibition of nonsense mediated decay and microarray analysis. Cancer Genet Cytogenet 2005; 161:97-103.
• Ionov Y, Nowak N, Perucho M, Markowitz S, Cowell JK. Manipulation of nonsense mediated decay identifies gene mutations in colon cancer cells with microsatellite instability. Oncogene 2004; 23:639-645.
• Ionov Y, Matsui S, Cowell JK. A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability. Proc Natl Acad Sci USA 2004; 101:1273-1278.
• Ionov Y, Le X, Tunquist BJ, Sweetenham J, Sachs T, Ryder J, Johnson T, Lilly MB, Kraft AS. Pim-1 protein kinase is nuclear in Burkitt?s lymphoma: nuclear localization is necessary for its biologic effects. Anticancer Res 2003; 23:167-178.
• Ionov Y, Yamamoto H, Krajewski S, Reed JC,Perucho M. Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci U S A 2000; 97:10872-10877.
• Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, Perucho M. Somatic frameshift mutations in BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275:967-969.
• Shibata D, Peinado MA, Ionov Y, Malkhosyan S, Perucho M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nat Genet 1994; 6:273-28.
• Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993; 363:558-561.