PubMed Health⌕ Search

Biomedical subjects

Eiki Kanbe

Publications and source records attributed to Eiki Kanbe.

6 recordsLinked to original sources
PubMed2006

A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis.

The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.

Alternative Splicing↗
PubMed2004

Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development.

Normal blood-cell differentiation is controlled by regulated gene expression and signal transduction. Transcription deregulation due to chromosomal translocation is a common theme in hematopoietic neoplasms. AML1-ETO, which is a fusion protein generated by the 8;21 translocation that is commonly associated with the development of acute myeloid leukemia, fuses the AML1 runx family DNA-binding transcription factor to the ETO corepressor that associates with histone deacetylase complexes. Analyses have demonstrated that AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. Here, we report that the loss of the molecular events of AML1-ETO C-terminal NCoR/SMRT-interacting domain transforms AML1-ETO into a potent leukemogenic protein. Contrary to full-length AML1-ETO, the truncated form promotes in vitro growth and does not obstruct the cell-cycle machinery. These observations suggest a previously uncharacterized mechanism of tumorigenesis, in which secondary mutation(s) in molecular events disrupting the function of a domain of the oncogene promote the development of malignancy.

Animals↗
PubMed2004

p53 alterations in myeloid leukemia.

Although most solid tumors contain inactivating mutations of the p53 tumor suppressor, hematological malignancies do not contain frequent alterations in the p53 gene (<20%). How these tumors arise in the presence of a super tumor suppressor like p53 remains to be elucidated. Given the number of downstream effectors of p53, it is likely that critical targets of p53 are inactivated in leukemia, bypassing the requirement for p53 gene mutations in these tumors. This review describes new biochemical and transcriptional activities of p53 as well as the status of p53 in acute myelogenous leukemia and chronic myelogenous leukemia.

Acute Disease↗
PubMed2003

DR1-like element in human topoisomerase IIalpha gene involved in enhancement of etoposide-induced apoptosis by PPARgamma ligand.

OBJECTIVE: The nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) ligands may enhance the etoposide-induced apoptosis by modulating the topoisomerase (Topo) IIalpha expression through binding to direct repeat 1 (DR1)-like element. METHODS: To investigate the effect of etoposide-induced apoptosis by PPARgamma ligands, leukemia cell lines were treated with troglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) in the presence of etoposide and studied about various biological responses. RESULTS: We found the enhancement of etoposide-induced apoptosis by PPARgamma ligands in several leukemia cell lines, which was dependent on the expression of PPARgamma and specific for TopoIIalpha inhibitor. We also observed the increased expression of TopoIIalpha protein by 15d-PGJ2 in Jurkat and HUVEC cells, which might lead to the increased sensitivity to etoposide. Furthermore, we demonstrated that 15d-PGJ2 enhanced the promoter activity of human TopoIIalpha promoter construct with a DR1-like site by sevenfold when expressed with PPARgamma and RXRalpha. The mutation of DR1-like site decreased the promoter activity, although the direct binding between DR1-like site and PPARgamma/RXRalpha heterodimer was not demonstrated. CONCLUSIONS: We conclude that the induction of TopoIIalpha expression by PPARgamma ligands via DR1-like site is an important mechanism for the enhancement of etoposide-induced apoptosis and a DR1-like site in TopoIIalpha promoter is involved in transcriptional regulation dependent on PPARgamma ligands and PPARgamma/RXRalpha heterodimer.

Antigens, Neoplasm↗
PubMedDate not supplied

A simple and quick method to concentrate MSCV retrovirus.

Retroviral-mediated gene transfer is widely used to express proteins in hematopoietic cells for the analysis of their effects on blood cell proliferation, differentiation, and biological function. The efficiency of gene transfer depends on the concentration of retrovirus in cell culture medium during infection. Here, we report one simple and quick method to increase titers of retrovirus. Centrifugation of murine stem cell virus (MSCV) in either microcentrifuge or high-speed centrifuge for only 1 h can significantly concentrate retrovirus at the bottom of the tube. The resuspended retrovirus can be used effectively to infect target cells in gene transfer experiments.

Animals↗