Epigenetic Determinants of Corticosteroid Responsiveness in Diamond Blackfan Anemia Syndrome
Abstract
Diamond Blackfan anemia syndrome (DBAS) is an inherited bone marrow failure syndrome (IBMFS) where inadequate red blood cell production is the major abnormal finding. Thus, many DBAS patients have life-long, severe anemia that requires treatment with chronic steroid medications, regular red blood cell transfusions, or bone marrow transplantation. Like other IBMFSs, DBAS patients are also more likely to have an array of specific physical developmental defects identified after birth and are predisposed to increased rates of development of certain cancers throughout their lives. Intensive research over the past 20+ years has defined the genetic defect in the majority of patients. DBAS genetics are truly complicated, with mutations in over 27 genes identifiable in roughly 80% of DBAS patients. The common thread running among these gene mutations is that nearly all reduce production of the ribosome, which is the site of protein production in all cells. Since normal cell growth and function in all tissues requires adequate protein production, the reason that DBAS patients show mostly anemia is not well understood. This finding suggests that, at least in many non-bone marrow tissues, there are innate compensatory mechanisms that can overcome protein production defects. In addition to defining the molecular site of the underlying defect in DBAS, these genetic studies have enabled detailed study of how DBAS gene mutations develop, pass, and are shared among family members. These studies have revealed that DBAS gene mutations are often present in family members without anemia, underscoring and expanding the clinical observation that DBAS disease manifestations can be quite variable. One commonly observed variable feature lies in individual patient responses to medical therapies. Chronic steroid treatment has been used in DBA for over 60 years, but not all patients benefit from this treatment modality. Some patients do not respond at all, some respond but the high doses required to correct the anemia are too toxic, some can stay on very low dose steroids for very long periods with minimal or no anemia, and some who have been responsive to steroids over many years will ultimately lose that response in adulthood. The basis for this variability in steroid response specifically, and other, more generally observed features of DBAS such as clinically unaffected family members, is not understood. However, these observations have a very important implication with direct relevance to therapy for anemia in DBAS: A ribosomal gene mutation is not a mandatory sentence to severe anemia. In many patients, the developing red cells clearly employ intrinsic compensatory mechanisms that are conceptually if not mechanistically akin to compensation in non-bone marrow tissues. Understanding the variable steroid response in DBAS will have direct application in the Bone Marrow Failure Research Program Idea Development Focus Area of finding effective BMF treatments and cures in several ways. Features that regulate this response could immediately be used to as biomarkers for diagnostic testing to predict steroid response, thus avoiding toxic steroid exposure in many DBAS patients. Identification of the key steroid regulator pathways would permit design and testing of novel therapeutic approaches to switch on steroid response, thus allowing combination therapies in previously nonresponsive patients. A similar strategy could augment steroid response, thus permitting reduced and less toxic doses of steroids to be used broadly in DBAS. Finally, such red cell escape pathways would be ideal targets for gene therapy in DBA, where the high number of involved genes presently precludes direct therapy of the mutated DBAS gene in all but the most common types. One of the primary limitations to understanding this response has been availability of appropriate scientific models to probe these differences. An important innovative aspect of this
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310640
Entities
People
- Jason Farrar
Organizations
- United States Army