CANCER GENOMICS DIVISION

8.CANCER GENOMICS DIVISION

    Current research in the Cancer Genomics Division focuses on the positional cloning of leukemia-related genes, and tumor suppressor genes, and the screening of SNPs associated with the susceptibility to various cancers. Functional analyses of several tumor-associated gene products including AML1 are also in progress.
Genome Analysis and Genetic Alterations in Human Cancers

    Human chromosome 11q has been shown to contain several tumor suppressor genes for neuroblastoma (NBL), lung cancer, breast cancer, and endometrial cancer. To isolate candidate tumor suppressor genes, detailed LOH analyses were carried out. This allowed us to narrow down the regions to 1.2 Mb, 0.3 Mb and 1.0 Mb for NBL, endometrial cancer and esophageal squamous cancer, respectively. Sequence analysis of the respective region was conducted in collaboration with RIKEN, Genome Sciences Center using a BAC contig previously constructed by us. Isolation of cDNAs for the genes predicted by a computer analysis allowed us to construct almost complete transcript maps for the relevant regions. Amplification of chromosomal DNA is thought to be one of the mechanisms that activates cancer-related genes in tumors. We identified high copy-number amplification at 11q21-q23 in cell lines derived from esophageal squamous cell carcinomas using comparative genomic hybridization. To identify the most likely target(s) for amplification at 11q21-q23, expression levels of 11 known genes and one uncharacterized transcript present within the 1.8-Mb commonly amplified region were measured. This led to the finding that only cIAP1, a member of the IAP (antiapoptotic) gene family, was consistently overexpressed in cell lines.⁽¹¹⁷⁾ Genetic aberrations frequently found in NBL are loss of the distal part of the short arm of chromosome 1, the MYCN oncogene and 17q gain, all of which are associated with an unfavorable prognosis. Chen et al. identified a homozygously deleted region within the smallest region at 1p36.2-p6.3 in NB cell lines. The estimated length of the deleted region was 500 kb.⁽¹¹⁸⁾ Our effort to construct a physical map of the 1p35-p36 region contributed to this work.⁽¹¹⁹⁾
    The t(8;22)(p11;q13) is found in rare cases of AML. The breakpoints of the translocation on chromosomes 8 and 22 correspond to the MOZ and p300 loci, respectively. In addition, features of this subgroup of AML, including monocytic arrest and erythrophagocytosis resemble those of classical AML with t(8;16)(p11.2;p3.3), in which MOZ is fused to CBP. Molecular analysis of the translocation breakpoint revealed a novel fusion of MOZ to p300 in AML with t(8;2)(p11.2;q13.1) as repredicted.
    The NUP98 gene is frequently targeted in several chromosome translocations associated with acute leukemia. Fluorescence in situ hybridization analysis of t(11;20) (p15;q11.2) showed that the NUP98 gene was split and involved in this translocation. This is the first report of t(11;21)(p15;q11.2) involving the NUP98 gene in overt leukemia.⁽¹²⁰⁾
The AML1 transcription factor complex

    Mass spetrometric analysis of peptides derived from several proteins found in purified AML1 complex revealed that MOZ is part of the AML1 complex and strongly stimulates AML1-mediated transcription.⁽¹²¹⁾ This, combined with the fact that aberration of MOZ is causative of leukemogenesis, suggests vital roles of MOZ at many steps in regulating differentiation and differentiation of hematopoietic cells.
Drug design-tool using VR technology

    We designed two concept of a computer aided moelecular modeling system using virtual reality technology. Although it is still a prototype, the most chracteristic function of the system is enabling its user to "touch" and "feel" the electrostatic potential field of a protein or a drug molecule. The user can scan the surface of a protein using a globular probe, which is given an electrostatic charge, controlled by a force feedback device. We also developed a binding simulator with which we can bind a small molecule (drug) to a large molecule (protein). Our prototype system has the potential to serve as a new application method as well as being applicable to conventional VR techniques, especially to force feedback technology.⁽¹²²⁾




8.CANCER GENOMICS DIVISION



	Current research in the Cancer Genomics Division focuses on the positional cloning of leukemia-related genes, and tumor suppressor genes, and the screening of SNPs associated with the susceptibility to various cancers. Functional analyses of several tumor-associated gene products including AML1 are also in progress. Genome Analysis and Genetic Alterations in Human Cancers Human chromosome 11q has been shown to contain several tumor suppressor genes for neuroblastoma (NBL), lung cancer, breast cancer, and endometrial cancer. To isolate candidate tumor suppressor genes, detailed LOH analyses were carried out. This allowed us to narrow down the regions to 1.2 Mb, 0.3 Mb and 1.0 Mb for NBL, endometrial cancer and esophageal squamous cancer, respectively. Sequence analysis of the respective region was conducted in collaboration with RIKEN, Genome Sciences Center using a BAC contig previously constructed by us. Isolation of cDNAs for the genes predicted by a computer analysis allowed us to construct almost complete transcript maps for the relevant regions. Amplification of chromosomal DNA is thought to be one of the mechanisms that activates cancer-related genes in tumors. We identified high copy-number amplification at 11q21-q23 in cell lines derived from esophageal squamous cell carcinomas using comparative genomic hybridization. To identify the most likely target(s) for amplification at 11q21-q23, expression levels of 11 known genes and one uncharacterized transcript present within the 1.8-Mb commonly amplified region were measured. This led to the finding that only cIAP1, a member of the IAP (antiapoptotic) gene family, was consistently overexpressed in cell lines.⁽¹¹⁷⁾ Genetic aberrations frequently found in NBL are loss of the distal part of the short arm of chromosome 1, the MYCN oncogene and 17q gain, all of which are associated with an unfavorable prognosis. Chen et al. identified a homozygously deleted region within the smallest region at 1p36.2-p6.3 in NB cell lines. The estimated length of the deleted region was 500 kb.⁽¹¹⁸⁾ Our effort to construct a physical map of the 1p35-p36 region contributed to this work.⁽¹¹⁹⁾ The t(8;22)(p11;q13) is found in rare cases of AML. The breakpoints of the translocation on chromosomes 8 and 22 correspond to the MOZ and p300 loci, respectively. In addition, features of this subgroup of AML, including monocytic arrest and erythrophagocytosis resemble those of classical AML with t(8;16)(p11.2;p3.3), in which MOZ is fused to CBP. Molecular analysis of the translocation breakpoint revealed a novel fusion of MOZ to p300 in AML with t(8;2)(p11.2;q13.1) as repredicted. The NUP98 gene is frequently targeted in several chromosome translocations associated with acute leukemia. Fluorescence in situ hybridization analysis of t(11;20) (p15;q11.2) showed that the NUP98 gene was split and involved in this translocation. This is the first report of t(11;21)(p15;q11.2) involving the NUP98 gene in overt leukemia.⁽¹²⁰⁾ The AML1 transcription factor complex Mass spetrometric analysis of peptides derived from several proteins found in purified AML1 complex revealed that MOZ is part of the AML1 complex and strongly stimulates AML1-mediated transcription.⁽¹²¹⁾ This, combined with the fact that aberration of MOZ is causative of leukemogenesis, suggests vital roles of MOZ at many steps in regulating differentiation and differentiation of hematopoietic cells. Drug design-tool using VR technology We designed two concept of a computer aided moelecular modeling system using virtual reality technology. Although it is still a prototype, the most chracteristic function of the system is enabling its user to "touch" and "feel" the electrostatic potential field of a protein or a drug molecule. The user can scan the surface of a protein using a globular probe, which is given an electrostatic charge, controlled by a force feedback device. We also developed a binding simulator with which we can bind a small molecule (drug) to a large molecule (protein). Our prototype system has the potential to serve as a new application method as well as being applicable to conventional VR techniques, especially to force feedback technology.⁽¹²²⁾