2005 Fiscal Year Final Research Report Summary
Mechanism of leukemogenesis with chromosomal translocation induced by oncogenic fusion genes and proliferation-associated genes
| Project/Area Number |
15390322
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | Kyoto Prefectural University of Medicine (2004-2005)
The University of Tokyo (2003) |
|---|
Principal Investigator |
TAKI Tomohiko Kyoto Pref.Univ.of Med., Grad.Sch.of Med.Sci., Dept of Mol.Lab.Med., Associate Professor, 医学研究科, 講師 (50322053)
|
|---|
| Project Period (FY) |
2003 – 2005
|
| Keywords | leukemia / chromosomal translocation / chimeric gene / proliferation-associated gene / MLL / FLT3 / KIT / t(8;21) |
|---|
| Research Abstract |
We analyzed a complex translocation involving chromosomes 7, 11, 19 and 22 in infant acute monocytic leukemia, and identified that the MLL gene on 11q23 was fused to the unconventional myosin type 1F, MYO1F, gene on 19p13.2-13.3. The MYO1F gene bears no homology with the partner genes of MLL previously described, therefore, this finding would provide new insights into leukemogenesis associated with MLL.
We next performed mutational analysis of FLT3 genes in childhood acute lymphoblastic leukemia (ALL), and found FLT3-D835/I836 mutations in 8(18.2%) of 44 infants with ALL with MLL rearrangements. In mouse model, MLL-SEPT6 induced myeloproliferative disease with long latency, but not acute leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3(FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. These findings showed direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.
We also performed mutational analysis of KIT and FLT3 genes in childhood acute myeloid leukemia (AML) with t(8;21), and found the kinase domain mutations of the KIT gene in 8 (17.4%) of 46 patients. FLT3 internal tandem duplication was found in only 2 (4.3%) patients. Significant differences between patients with or without KIT mutations were observed in the 4-year overall survival (50.0% versus 97.4%, P<0.001), disease-free survival (37.5% versus 94.7%, P<0.001) and relapse rate (47.0% versus 2.7%, P<0.001). Although patients with t(8;21)-AML are generally considered to have a good prognosis, these results suggested that KIT mutations are strongly associated with a poor prognosis in pediatric t(8;21)-AML.
|
Research Products
(25 results)
-
-
-
-
-
[Journal Article] KIT mutation, and not FLT3 internal tandem duplication, is strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21) : a study of the Japanese Childhood AML Cooperative Study Group.2006
Author(s)
Shimada A, Taki T, Tabuchi K, Tawa A, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y.
-
Journal Title
Blood 107
Pages: 1806-1809
Description
「研究成果報告書概要(欧文)」より
-
[Journal Article] Mutations of the PTPN 11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies.2006
Author(s)
Chen Y, Takita J, Hiwatari M, Igarashi T, Hanada R, Kikuchi A, Hongo T, Taki T, Ogasawara M, Shimada A, Hayashi Y.
-
Journal Title
Genes Chromosomes Cancer 45
Pages: 583-591
Description
「研究成果報告書概要(欧文)」より
-
-
-
-
-
-
-
-
-
[Journal Article] Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia.2005
Author(s)
Urano A, Endoh M, Wada T, Morikawa Y, Itoh M, Kataoka Y, Taki T, Akazawa H, Nakajima H, Komuro I, Yoshida N, Hayashi Y, Handa H, Kitamura T, Nosaka T.
-
Journal Title
Mol Cell Biol 25
Pages: 6834-6845
Description
「研究成果報告書概要(欧文)」より
-
-
[Journal Article] The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7, 11, 19 and 22.2005
Author(s)
Taki T, Akiyama M, Saito S, Ono R, Taniwaki M, Kato Y, Yuza Y, Eto Y, Hayashi Y.
-
Journal Title
Oncogene 24
Pages: 5191-5197
Description
「研究成果報告書概要(欧文)」より
-
[Journal Article] Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4.2005
Author(s)
Ono R, Ihara M, Nakajima H, Ozaki K, Kataoka-Fujiwara Y, Taki T, Nagata K, Inagaki M, Yoshida N, Kitamura T, Hayashi Y, Kinoshita M, Nosaka T.
-
Journal Title
Mol Cell Biol 25
Pages: 10965-10978
Description
「研究成果報告書概要(欧文)」より
-
-
-
-
-
[Journal Article] Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements.2003
Author(s)
Tsutsumi S, Taketani T, Nishimura K, Ge X, Taki T, Sugita K, Ishii E, Hanada R, Ohki M, Aburatani H, Hayashi Y.
-
Journal Title
Cancer Res 63
Pages: 4882-4887
Description
「研究成果報告書概要(欧文)」より
-
[Journal Article] Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.2003
Author(s)
Xu G, Kanezaki R, Told T, Hayashi Y, Kamio T, Terui K, Taketani T, Taki T, Mitui T, Koike K, Kato K, Imaizumi M, Sekine I, Ikeda Y, Hanada R, Sako M, Kudo N, Kojima S, Yamamoto M, Ito E.
-
Journal Title
Blood 102
Pages: 2960-2968
Description
「研究成果報告書概要(欧文)」より
-
