SummaryDiamond Blackfan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA affects about seven per million live births and presents during the first year of life. However, as mutated genes have been discovered in DBA, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.

We present evidence that both corepressors SMRT and N-CoR exist in large protein complexes with estimated sizes of 1.5±2 MDa in HeLa nuclear extracts. Using a combination of conventional and immunoaf®nity chromatography, we have successfully isolated a SMRT complex and identi®ed histone deacetylase 3 (HDAC3) and transducin (b)-like I (TBL1), a WD-40 repeat-containing protein, as the subunits of the puri®ed SMRT complex. We show that the HDAC3-containing SMRT and N-CoR complexes can bind to unliganded thyroid hormone receptors (TRs) in vitro. We demonstrate further that in Xenopus oocytes, both SMRT and N-CoR also associate with HDAC3 in large protein complexes and that injection of antibodies against HDAC3 or SMRT/N-CoR led to a partial relief of repression by unliganded TR/RXR. These ®ndings thus establish both SMRT and N-CoR complexes as bona ®de HDAC-containing complexes and shed new light on the molecular pathways by which N-CoR and SMRT function in transcriptional repression.

The t(8;21) translocation between two genes known as AML1 and ETO is seen in approximately 12-15% of all acute myeloid leukemia (AML) and is the second-mostfrequently observed nonrandom genetic alteration associated with AML. AML1 up-regulates a number of target genes critical to normal hematopoiesis, whereas the AML1͞ETO fusion interferes with this trans-activation. We discovered that the fusion partner ETO binds to the human homolog of the murine nuclear receptor corepressor (N-CoR). The interaction is mediated by two unusual zinc finger motifs present at the carboxyl terminus of ETO. Human N-CoR (HuN-CoR), which we cloned and sequenced in its entirety, encodes a 2,440-amino acid polypeptide and has a central domain that binds ETO. N-CoR, mammalian Sin3 (mSin3A and B), and histone deacetylase 1 (HDAC1) form a complex that alters chromatin structure and mediates transcriptional repression by nuclear receptors and by a number of oncoregulatory proteins. We found that ETO, through its interaction with the N-CoR͞mSin3͞HDAC1 complex, is also a potent repressor of transcription. This observation provides a mechanism for how the AML1͞ETO fusion may inhibit expression of AML1-responsive target genes and disturb normal hematopoiesis.

Shwachman-Diamond syndrome (SDS) is