Recent insights into inherited bone marrow failure syndromes

Abstract

Purpose of review: Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. The purpose of this review is to highlight novel findings in recent years and their impact on the understanding of IBMFS.

Recent findings: Mutations in over 80 different genes have been associated with the development of bone marrow failure (BMF). The products of the genes mutated in IBMFS frequently participate in housekeeping pathways, which are important for cell growth and division rather than being specific for hematopoiesis. The common theme of these pathways, when disturbed, is the activation of p53, leading to cell cycle arrest, senescence, and cell death. With continued improvement in therapy for IBMFS, late complications, such as development of malignancies, are seen more frequently. This highlights the importance of understanding the affected pathways and their roles in cancer development.

Summary: The recent advancement of our understanding of IBMFS has come largely through the identification of the genetic lesions responsible for disease and the investigations of their pathways. Applied in clinical practice, these findings make it possible to unambiguously identify mutation carriers even before the development of BMF and exclude or confirm a suspected clinical diagnosis for many of the more common IBMFS. The further characterization of the pathways leading to IBMFS is likely to reveal novel targets for screening tests, prognostic biomarkers, and improved and specific therapeutics.

Figure 1. DNA repair and FANC proteins

After DNA damage, the Ataxia Telangiectasia and RAD3-related kinase (ATR) activates the FA core complex (consisting of FANC A/B/C/E/F/G/L/M) by phosphorylation (ph). The core complex then acts as a ubiquitin ligase and monoubiquinates (ub) FANCD2 and FANCI. This monoubiquinated complex then is targeted to chromatin where it forms a complex with additional FA proteins and DNA repair proteins. DNA repair occurs through a variety of mechanisms. FANC D2/I are then deubiquinated, allowing their release from chromatin. Mutations in any of the FANC proteins will lead to defective DNA repair.

Figure 2. Telomere biology

Telomeres are at the ends of linear chromosomes and are composed of many tandem repeats of a hexanucleotide and associated proteins, called the shelterin complex. As telomeres shorten with cell replication, the telomerase complex is responsible for the elongation of telomeres by adding telomeric repeats to the ends of telomeres. Six of the DC gene products are a part of the telomerase complex (Dyskerin, TERT, TERC, NHP2, NOP10, and WDR79/TCAB1). The seventh (TIN2) is part of the shelterin protein complex.

Figure 3. Eukaryotic ribosome biogenesis

This process requires the coordinated synthesis of 4 ribosomal rRNAs (18S, 28S, 5.8S, 5S), several additional core ribosomal proteins and other associated proteins. Several diseases are implicated along the process of ribosome biogenesis, including Diamond-Blackfan Anemia (DBA), Shwachman Diamond Syndrome SDS), and Dyskeratosis Congenita (DC) secondary to DKC1 mutations.

Figure 4

Findings in the clinical history, physical exam, and family history that can provide clues to IBMFs. Suggested laboratory testing is also listed. Key: CBC=complete blood count, BUN=blood urea nitrogen, HIV=human immunodeficiency virus, EBV=Epstein Barr virus, CMV=cytomegalovirus, PNH=paroxysmal nocturnal hemoglobinuria, ADA= red cell adenosine deaminase activity, HLA=human leukocyte antigen

Figure 5. Biologic Pathways Involved in IBMFs

The pathways affected in the major forms of IBMFS are house-keeping pathways important for the growth and cell division of all cells: Defective DNA repair pathways is responsible for Fanconi Anemia, defective telomere maintenance causes Dyskeratosis Congenita, defective ribosomal processing is seen in Diamond-Blackfan Anemia, and is also thought to have implications in Shwachmann Diamond Syndrome and Dyskeratosis Congenita. Unfolded protein response is involved in some forms of Severe Congenital Neutropenia and is thought to play a role in apoptosis of granulocytic precursors. Additional pathways remain to be determined. The pathways involved in the IBMFs all lead to the activation of p53 causing cell cycle arrest, cell senescence or cell death, which are all features of bone marrow failure. Interestingly what these pathways also share is a predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the pathways(s) of leukemic transformations remain to be determined. Key: MDS=myelodysplastic syndrome, AML=Acute myeloid leukemia