Bcl11b mutations identified in murine lymphomas increase the proliferation rate of hematopoietic progenitor cells.
BACKGROUND
The telomeric region of mouse chromosome 12 has previously shown frequent allelic loss in murine lymphoma. The Bcl11b gene has been identified and suggested as a candidate tumor suppressor gene within this region. In this study, we aimed to elucidate whether Bcl11b is mutated in lymphomas with allelic loss, and whether the mutations we detected conferred any effect on cell proliferation and apoptosis.


METHODS
Mouse lymphomas induced by 1,3-butadiene or 2',3'-dideoxycytidine were analysed for mutations in the Bcl11b gene using single strand conformation analysis and direct DNA sequencing. Effects on cell proliferation by the detected mutations were studied by expressing wild-type and mutant Bcl11b in the cytokine-dependent hematopoietic progenitor cell line FDC-P1, lacking endogenous Bcl11b expression.


RESULTS
Missense and frameshift (FS) mutations were identified in 7 of 47 tumors (15%). Interestingly, all mutations were found between amino acids 778-844 which encode the three C-terminal DNA-binding zinc fingers. In FDC-P1 cells, wild-type Bcl11b suppressed cell proliferation, whereas the mutated versions (S778N, K828T, Y844C and FS823) enhanced proliferation several-fold.


CONCLUSIONS
The genetic alterations detected in this study suggest that the three C-terminal zinc fingers of Bcl11b are important for the DNA-binding. Cell proliferation was suppressed by overexpression of wild-type Bcl11b but enhanced by mutant Bcl11b, indicating that these mutations may be an important contributing factor to lymphomagenesis in a subset of tumors.
Karlsson
Anneli
A
Division of Cell Biology, Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. annka@ibk.liu.se
Nordigården
Amanda
A
Jönsson
Jan-Ingvar
JI
Söderkvist
Peter
P
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D016335:Zinc Fingers
C511143:Bcl11b protein, mouse; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins