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Lack of the Polycomb-group gene rae28 causes maturation arrest at the early B-cell developmental stage
1Department of Medical Genetics and Molecular Cell Biology, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka 565-0871, Japan.
Abstract:
The rae28 gene (rae28) is a murine homologue of the Drosophila polyhomeotic gene, which is a member of the Polycomb-group genes. In this study, we examined the role of rae28 in lymphocyte development. Because homozygous rae28-deficient (rae28-/-) mice died in the perinatal period, we examined lymphocyte development by generating chimeric mice reconstituted with green fluorescence protein-labeled mutant fetal liver cells as well as in in vitro culture systems. We further examined RAE28 expression by reverse transcriptase polymerase chain reaction assay in human leukemic cells with B-lineage acute lymphoblastic leukemia (ALL). Severe B-cell maturation arrest was observed in rae28-/- between pro- and pre-B lymphocyte stages. B-cell development was also delayed in heterozygous neonates. Furthermore, interleukin-7-dependent colony-forming ability was impaired not only in homozygous lymphocytes but also in heterozygotes. Its human homologue, RAE28, is located on chromosome 12p13, which frequently is associated with chromosomal abnormalities and loss of heterozygosity in patients with hematologic malignancies. To determine whether a link exists between RAE28 and leukemia, we examined RAE28 expression in leukemic cells from pediatric patients with B-lineage ALL. RAE28 expression was not detected in four B-cell precursor ALL cases of a total of 43 examined, although RAE28 is normally expressed constitutively during the process of B-cell maturation as assessed in isolated cell populations. rae28 plays an important role in the early B-cell developmental stage in a gene dosage-dependent manner. Furthermore, the human RAE28 locus may provide a candidate gene causing the molecular pathogenesis of childhood B-cell precursor ALL.
Insights
The rae28 gene is crucial for early B-cell development. Loss of rae28 function severely impairs B-cell maturation and interleukin-7 response, suggesting its role in B-cell precursor acute lymphoblastic leukemia.
Area of Science:
- Developmental biology
- Immunology
- Genetics
Background:
- The rae28 gene is a murine homologue of Drosophila polyhomeotic, part of the Polycomb-group genes.
- Polycomb-group genes are critical regulators of gene expression during development.
Purpose of the Study:
- To investigate the role of rae28 in lymphocyte development.
- To explore the potential link between human RAE28 and B-cell acute lymphoblastic leukemia (ALL).
Main Methods:
- Generation of chimeric mice using green fluorescence protein-labeled rae28-deficient fetal liver cells.
- In vitro culture systems to assess lymphocyte development.
- Reverse transcriptase polymerase chain reaction (RT-PCR) to analyze RAE28 expression in human leukemic cells.
Main Results:
- Homozygous rae28-deficient mice exhibited severe B-cell maturation arrest at the pro- to pre-B lymphocyte stages.
- Heterozygous neonates showed delayed B-cell development and impaired interleukin-7-dependent colony-forming ability.
- RAE28 expression was undetectable in a subset of pediatric B-cell precursor ALL cases, despite its constitutive expression during normal B-cell maturation.
Conclusions:
- Rae28 plays a critical, gene dosage-dependent role in early B-cell development.
- The human RAE28 locus on chromosome 12p13 is a candidate gene involved in the pathogenesis of childhood B-cell precursor ALL.