| Co-Investigator(Kenkyū-buntansha) |
KAWAGUCHI Hiroyuki The Univ. of Tokyo(Hospital),research associate, 医学部・附属病院, 助手 (00313130)
TAKI Tomohiko The Univ. of Tokyo(Hospital), research associate, 医学部・附属病院, 助手 (50322053)
HAYASHI Yasuhide The Univ. of Tokyo(Hospital), Lecturer, 医学部・附属病院, 講師 (30238133)
小林 美由紀 東京大学, 医学部・附属病院, 講師 (60205391)
別所 文雄 東京大学, 医学部・附属病院, 助教授 (40010285)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
t(10;11) is strongly associated with complex translocations. We analyzed a patient of acute myeloid leukemia (AML) with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl interactor 1 (Abi-1), fused with MIL. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1 fusion transcript in this patient was formed by an alternatively spliced ABI-1. In-frame MLL-ABI-1 fusion transcripts combine the MLL with polyproline stretches and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL.
Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements is characterized by early pre-B phenotype (CD10(-)/CD19(+)) and poor treatment outcome. The t(4;11), creating MLL-AF4 chimeric transcripts, is the predominant 11q23 chromosome translocation in infant ALL and is associated with extremely poor prognosis as compared with other 11q23 translocat
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ions. We analyzed an infant early preB ALL with ins(5;11)(q31;q13q23) and identified the AF5q31 gene on chromosome 5q31 as a fusion partner of the MLL gene. The AF5q31 gene, which encoded a protein of 1,163 aa, was located in the vicinity of the cytokine cluster region of chromosome 5q31 and contained at least 16 exons. The AF5q31 gene was expressed in fetal heart, lung, and brain at relatively high levels and fetal liver at a low level, but the expression in these tissues decreased in adults. The AF5q31 protein was homologous to AF4-related proteins, including AF4, LAF4, and FMR2. The AF5q31 and AF4 proteins had three homologous regions, including the transactivation domain of AF4, and the breakpoint of AF5q31 was located within the region homologous to the transactivation domain of AF4. Furthermore, the clinical features of this patient with the MLL-AF5q31 fusion transcript, characterized by the early pre-B phenotype (CD10(-)/CD19(+)) and poor outcome, were similar to those of patients having MLL-AF4 chimeric transcripts. These findings suggest that AF5q31 and AF4 might define a new family particularly involved in the pathogenesis of 11q23-associated-ALL.
t(X;11) is a recurrent translocation in pediatric AML. We showed that the MLL gene on 11q23 was fused to the SEPTIN6 gene on Xq24, a human homologue to mouse Septin6, in three de novo infant AML with complex chromosomal abnormalities involving 11q23 and Xq22-24. SEPTIN6 consisted of at least 12 exons and was predicted to encode at least two types of proteins by alternative splicing. Expression of approximately 2.3-, 3.1-, and 4.6-kb SEPTIN6 transcripts was simultaneously detected in fetal lung, liver, and brain, in all of the adult tissues except brain, and in ALL and AML cell lines. However, the expression of an approximately 2.7-kb transcript was detected alone in fetal heart and adult brain. The SEPTIN6 protein is homologous to septin family members including CDCREL1 and AF17q25/MSF, which generate fusion products with MLL. The MLL-SEPTIN6 fusion proteins contain almost the entire septin protein, similar to MLL-CDCREL1 and MLL-AF17q25/MSF. Notably, all three of the patients were diagnosed with M1 or M2. Combined present results and literatures suggest that AML with the MLL-SEPTIN6 fusion gene is a subset of infant AML, which differentiate into the myeloid lineage, although AML with other MLL fusion genes is capable of differentiating into the myelomonocytic or monocytic lineage. Less
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