Mutations in transcriptional regulators are frequently associated with hematological malignancies. For example, mutations in chromatin-bound ASXL1 occur in more than 10% of individuals with myelodysplastic syndrome (MDS) or myeloproliferative disease. In contrast, its binding partner, BAP1, with which ASXL1 forms a histone deubiquitinase, is often deleted in uveal melanoma and mesothelioma. Now, two papers report the effects of ASXL1 or BAP1 deficiency in myeloid cell transformation.

Omar Abdel-Wahab et al. (Cancer Cell 22, 180–193) report that silencing of ASXL1, but not BAP1, in hematopoietic cells increased the expression of the homeobox genes HOXA5–9. They found that ASXL1 binds the transcriptional repressor EZH2, and in the absence of ASXL1, EZH2 is lost from the posterior HOXA locus, which probably mediates the deregulated expression of HOXA5–9. Furthermore, ASXL1 knockdown reduced survival and accelerated a myeloproliferative disease caused by expression of an oncogenic N-Ras allele in mouse bone marrow cells.

Anwesha Dey et al. (Science, doi:10.1126/science.1221711) confirmed that conditional deletion of BAP1 in adult hematopoietic cells did not increase Hox gene expression but did cause a myeloproliferative disorder similar to that seen in individuals with chronic myelomonocytic leukemia (in which ASXL1 mutations are known to occur). They identified one patient with MDS with a heterozygous mutation in BAP1 and found reduced expression of BAP1 mRNA in bone marrow cells from patients with MDS compared with healthy individuals. The researchers found that BAP1 associates with the epigenetic regulator HCF-1 and with O-linked N-acetylglucosamine transferase (OGT), both of which were reduced in amount by BAP1 deletion. The authors propose that BAP1, OGT and HCF-1 form a complex on promoters, the loss of which contributes to deregulated gene expression and myeloproliferative disease.

The findings presented in these two reports confirm the importance of chromatin modifiers in hematopoietic malignancy and suggest complementary roles for ASXL1 and BAP1 in maintaining normal hematopoiesis.