Lack of the Polycomb-group gene rae28 causes maturation arrest at the early B-cell developmental stage

Objective. The rae28 gene (rae28) is a murine homologue of the Drosophila p olyhomeotic gene, which is a member of the Polycomb-group genes. In this st udy, we examined the role of rae28 in lymphocyte development, Materials and Methods. Because homozygous rae28-deficient (rae28(-/-)) mice died in the perinatal period, we examined lymphocyte development by genera ting chimeric mice reconstituted with green fluorescence protein-labeled mu tant fetal liver cells as well as in in vitro culture systems. We further e xamined RAE28 expression by reverse transcriptase polymerase chain reaction assay in human leukemic cells with B-lineage acute lymphoblastic leukemia (ALL). Results. Severe B-cell maturation arrest was observed in I rae28(-/-) betwe en 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 hut also in hetero zygotes. Its human homologue, RAE28, is located on chromosome 12p13, which frequently is associated with chromosomal abnormalities and loss of heteroz ygosity in patients with hematologic malignancies. To determine whether a l ink exists between RAE28 and leukemia, we examined RAE28 expression in leuk emic 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, Conclusions, rae28 plays an important role in the early B-cell developmenta l stage in a gene dosage-dependent manner. Furthermore, the human RAE28 loc us may provide a candidate gene causing the molecular pathogenesis of child hood B-cell precursor ALL. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc.