Abstract
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.