Diamond Blackfan anemia (DBA) is an inherited bone marrow failure and cancer predisposition syndrome characterized in most patients by severe anemia that requires long term treatment with red blood cell transfusions or corticosteroids, both treatments carrying significant and serious side-effects. The genetic cause for DBA is now established to stem in most cases from mutations in one among a family of genes responsible for forming the manufacturing plant present in all of an individual?s cells, the ribosome. Since ribosomes are needed in nearly all cell types, the reason that red cell precursors are preferentially affected in DBA is not well understood. Importantly, study of the natural history of patients and families with DBA reveals that unknown factors can modify the severity of the disease. Some individuals in a family carrying a DBA mutation may have classic, transfusion-dependent anemia while others, who share the same gene mutation, may be minimally affected, without anemia and subtle if any hematologic manifestations. In another circumstance, DBA patients who previously required significant medical treatment for DBA, such as dependence on red cell transfusions, may stop requiring medical treatment and maintain adequate red cell levels on their own for an indefinite period of time. This condition is termed ?hematologic remission? and unpredictably occurs in one out of every five to ten DBA patients who require treatment. It is also reversible, meaning that a patient who is in hematologic remission at one point may lose that remission and become dependent on medical therapy later, again in an unpredictable fashion. Along with other features, the reversible nature of hematologic remission in DBA suggests that it may be mediated by epigenetic factors in developing red cells or their progenitors. A confluence of novel methods including cell culture techniques that allow expansion of patient-derived human blood progenitor cells into red cells, technical innovations that allow genome-wide measurement of epigenomic factors from limited cell numbers, and systems-based computational methods for data analysis make detailed analysis of the molecular mechanisms underlying hematologic remission in DBA feasible for pursuit. In this innovative work, we focus on a single aim to develop new pathways for understanding the hematologic phenotype in DBA: definition of the epigenetic mechanisms of remission. Using genome-scale studies of DNA methylation, chromatin occupancy and characterization, and RNA transcription in red cell precursors from patients in hematologic remission, we will identify the changes in regulatory pathways that bypass the red cell defect in DBA. Findings from this study will thus identify new directions for developing medical therapies to ameliorate anemia in DBA. More broadly, this work will be important in understanding how tissue specificity is modulated in the human ribosomopathies.
Diamond Blackfan anemia (DBA) is genetic disorder of protein production manifesting as impaired red blood cell production that leads to severe anemia in most patients; however, compared to many patients who require bone marrow transplantation, life-long red-cell transfusions or toxic medical therapy to treat severe anemia, some individuals who inherit the abnormal DBA genes manifest minimal or no anemia (termed non- penetrance) while others only intermittently display severe anemia requiring treatment (a condition termed hematologic remission). Using red cell precursors derived from patients in hematologic remission, we will employ advanced genomic technologies to identify and modulate the intrinsic gene regulatory mechanisms that permit remission DBA red cell production to ?escape? from the underlying protein production defect. By identifying these innate escape pathways, this study has significant promise for finding new treatments for this life-altering/life-limiting disease, as well as broader implications for improved treatments for other forms of anemia and the general class of human diseases stemming from disorders of ribosome production, the ribosomopathies.
