The Role of Tumour Suppressors BAP1 and ASXL1 in Myelodysplasia

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of haematologic disorders characterised by clonal expansion of bone marrow myeloid cells that is associated with abnormal differentiation. These disorders are often associated with anaemia, neutropenia and thrombocytopenia and have the potential to evolve to acute myeloid leukemia. Studies have highlighted the role of epigenetic regulators in MDS and the loss of the tumour suppressor BRCA1-associated protein 1 (BAP1) was recently reported to cause myeloid transformation in a mouse model. BAP1-deficient mice recapitulate the features of human chronic myelomonocytic leukaemia, (an overlap syndrome of MDS and myeloproliferative neoplasms). BAP1 forms a complex with ASXL1 and is localised on many gene promoters; the complex controls gene regulation through deubiqutination. ASXL1 also has a BAP1-independent function in regulating gene expression through histone modification. In this study, I determined the spatiotemporal expression pattern of bap1 and asxl1 in zebrafish. Bap1 and asxl1 are both expressed in the anterior regions of the developing embryo. Although this appears to be mainly in the brain, it includes regions of anterior lateral plate mesoderm that are involved in early haematopoietic events. Furthermore, asxl1 was also expressed in the posterior blood island and caudal haematopoietic tissue posteriorally, which are important sites for blood development. The absence of bap1 expression in the posterior region raises the possibility that asxl1 may have roles in haematopoiesis that are independent of bap1. Antisense morpholino knockdown of bap1 or asxl1 altered the expression of some blood-related markers including gata1,lys and runx1, indicating that absence of bap1 or asxl1 can lead to developmental abnormalities in the erythroid and myeloid lineages, and in haematopoietic stem cells. Zebrafish bap1 and asxl1 morphants recapitulated features observed in Bap1 or Asxl1 deficient mice, which are recognised phenotypes of MDS. Overall, these results provide evidence of roles for bap1 and asxl1 during embryonic blood development and suggest that the zebrafish will be a useful model for examining how abnormalities in these epigenetic regulators lead to MDS. This may uncover new therapeutic opportunities.