2004 Fiscal Year Final Research Report Summary
Identification of the causative genes fox Down syndrome associated acute megakaryocytic leukemia
| Project/Area Number |
14370238
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | Hirosaki University |
|---|
Principal Investigator |
ITO Etsuro Hirosaki University, School of Medicine, Professor, 医学部, 教授 (20168339)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TOKI Tsutomu Hirosaki University, School of Medicine, Associate Professor, 医学部, 講師 (50195731)
TAKAHASHI Yoshihiro Hirosaki University, School of Medicine, Lecture, 医学部, 助手 (10333725)
|
|---|
| Project Period (FY) |
2002 – 2004
|
| Keywords | GATA1 / Bach1 / Down syndrome / Acute megakaryocytic leukemia / TMD / transcriptional factor / transgenic mouse |
|---|
| Research Abstract |
We performed this study to identify the causative genes for transient myeloproliferative disorder (TMD) in Down syndrome., and found the following results.
1.Analysis of the candidate of the causative genes for TMD.
We report here that mutations in the sequences corresponding to the N-terminal region in the GATA-1 gene were found in 21 out of 22 cases with TMD. We recently encountered identical twin females who had TMD with DS. Both patients had an identical mutation in the GATA-1 gene. Our results provide definitive evidence that GATA1 mutations occur in utero in cases of AMKL with DS.
2.cDNA cloning of the candidate genes for TMD on chromosome 21q11.2.
We isolated novel genes in the region of 21q11-21, the possible candidate location for TMD.
3.Generation of the model mouse for Down syndrome associated AMKL (DS-AMKL).
We generated transgenic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The transgenic mouse lines showed significant thrombocytopenia associated with impaired nuclear and cytoplasmic maturation of the megakaryocytes, and developed myelofibrosis. We crossed the BACH1 transgenic mice with GATA-1 knock down mice, and we are now in the process of analyzing these mice.
4.The analysis of the mechanisms of leukemogenesis by GATA-1 mutations.
For this purpose, we established DS-AMKL cell line, which expressed full length GATA-1. Furthermore, we successfully knocked down the expression of short form of GATA-1 by RNAi techniques.
|
