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| Status |
Public on Apr 03, 2007 |
| Title |
Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Acute lymphoblastic leukemia (ALL) cells are derived from B cell precursors in most cases and typically carry rearranged immunglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph-positive ALLs as compared to 6 of 80 Ph-negative ALLs. Forced expression of BCR-ABL1 in Ph-negative ALL cells and inhibition of the BCR-ABL1-kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph-positive ALL, IGH V region genes and BCL6 were mutated in many Ph-positive but unmutated in most Ph-negative cases. In addition, AID introduced DNA-single-strand breaks within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.
Keywords: gene expression array-based (RNA / in situ oligonucleotide)
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| Overall design |
To study the gene expression profile of two Ph-positive ALL cell lines (BV173 and SUP-B15) in the presence or absence of 10 μmol/l STI571 for 16 hours
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| Contributor(s) |
Feldhahn N, Henke N, Melchior K, Duy C, Soh BN, Klein F, von Levetzow G, Giebel B, Li A, Hofmann W, Jumaa H, Müschen M |
| Citation(s) |
17485517 |
| |
| Submission date |
Mar 04, 2007 |
| Last update date |
Dec 06, 2018 |
| Contact name |
Markus Müschen |
| E-mail(s) |
mmuschen@chla.usc.edu
|
| Phone |
+ 1 323 361 5592
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| Fax |
+1 323 361 1516
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| URL |
http://www.lymphocytes.de/
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| Organization name |
University of Southern California
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| Department |
Childrens Hospital Los Angeles
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| Lab |
Müschen Lab
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| Street address |
4650 Sunset Blvd
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90027 |
| Country |
USA |
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| Platforms (1) |
| GPL571 |
[HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA98333 |
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