Possible Involvement of Apoptotic Regulatory Pathways in the Leukemogenesis of Common ALL.
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概要
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Genes conserved in the evolution of multicellular organisms play critical roles in the apoptotic cell death pathways. For example, virtually all programmed cell deaths that occur during <I>Caenorhabditis elegans</I> development are regulated by the products of <I>ced</I>-3, <I>ced</I>-4 and <I>ced</I>-9 genes, while the homologues of these proteins, including bcl-2, bcl-x or interleukin-lβ converting enzyme (ICE) and its related cystein proteases, control mammalian apoptosis. Recently ces-2, a member of the basic region/leucine zipper (bZIP) transcription factor, was isolated from the <I>C. elegans</I> that regulates the expression of the genes involved in apoptotic pathways in specific neuron cells. Most strikingly, the amino acid sequence of ces-2 is highly homologous to mammalian hepatic leukemia factor (HLF) in the basic region, which contributes to leukemogenesis through forming a chimeric transcription factor with E2A (E12/E47) in t (17; 19) (q22; p13) -positive common ALL. To test the possibility that E2A-HLF chimera contributes to leukemogenesis through protecting cells from apoptosis, we established cells programmed to express a dominant-negative suppressor of E2A-HLF in human leukemia cells carrying t (17 ; 19). Cells rapidly died by apoptosis, suggesting that the chimeric oncoprotein affects cell survival rather than cell growth. Furthermore, expression of the E2A-HLF fusion transcription factor reversed IL-3-dependent apoptosis in murine pro-B lymphocytes. It is our current working hypothesis that the dysregulation of apoptotic pathways in pro-B cells, which are destined to death due to failure in immunoglobulin gene rearrangement, results in common ALL.
- 特定非営利活動法人 日本小児血液・がん学会の論文
特定非営利活動法人 日本小児血液・がん学会 | 論文
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