Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18-6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46-18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3-14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0-8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2-17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57-14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32-11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09-13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57-14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia, manifesting by differentiation blockage between the BFU-e/CFU-e developmental erythroid progenitor stages. In 50 % of the DBA cases, various malformations are noted. Strikingly, for a hematological disease with a relative erythroid tropism, DBA is due to ribosomal haploinsufficiency in 24 different ribosomal protein (RP) genes. A few other genes have been described in DBA-like disorders, but they do not fit into the classical DBA phenotype (Sankaran et al., 2012; van Dooijeweert et al., 2022; Toki et al., 2018; Kim et al., 2017 [1-4]). Haploinsufficiency in a RP gene leads to defective ribosomal RNA (rRNA) maturation, which is a hallmark of DBA. However, the mechanistic understandings of the erythroid tropism defect in DBA are still to be fully defined. Erythroid defect in DBA has been recently been linked in a non-exclusive manner to a number of mechanisms that include: 1) a defect in translation, in particular for the GATA1 erythroid gene; 2) a deficit of HSP70, the GATA1 chaperone, and 3) free heme toxicity. In addition, p53 activation in response to ribosomal stress is involved in DBA pathophysiology. The DBA phenotype may thus result from the combined contributions of various actors, which may explain the heterogenous phenotypes observed in DBA patients, even within the same family.

Clonal hematopoiesis in children and young adults differs from that occuring in the older adult population. A variety of stressors drive this phenomenon, sometimes independent of age-related processes. For the purposes of this review, we adopt the term clonal hematopoiesis in predisposed individuals (CHIPI) to differentiate it from classical, age-related clonal hematopoiesis of indeterminate potential (CHIP). Stress-induced CHIPI selection can be extrinsic, such as following immunologic, infectious, pharmacologic, or genotoxic exposures, or intrinsic, involving germline predisposition from inherited bone marrow failure syndromes. In these conditions, clonal advantage relates to adaptations allowing improved cell fitness despite intrinsic defects affecting proliferation and differentiation. In certain contexts, CHIPI can improve competitive fitness by compensating for germline defects; however, the downstream effects of clonal expansion are often unpredictable - they may either counteract the underlying pathology or worsen disease outcomes. A more complete understanding of how CHIPI arises in young people can lead to the definition of preleukemic states and strategies to assess risk, surveillance, and prevention to leukemic transformation. Our review summarizes current research on stress-induced clonal dynamics in individuals with germline predisposition syndromes.

The great pathologist Paul Ehrlich in Berlin is commonly credited with describing the first clear case of aplastic anaemia in 1888: a 21-year-old woman who presented with haemorrhage and signs and symptoms of severe anaemia, quickly succumbing to her illness. Ehrlich\'s description of this patient\'s background and clinical course allowed individual identification. Re-analysis of this case suggests an inherited bone marrow failure syndrome as a possible additional diagnosis.

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.

Up-front allogeneic haematopoietic stem cell transplantation (allo-HSCT) after a reduced intensity conditioning regimen is the standard treatment in children with acquired severe aplastic anaemia (aSAA) and inherited bone marrow failure syndromes (iBMFs) in the presence of a healthy matched related donor (MRD). The paper by Alsultan et al. report the safety and efficacy of MRD HSCT conditioned with low-dose cyclophosphamide, fludarabine and thymoglobulin in both aSAA and non-Fanconi iBMFs, strengthening the concept of the pivotal role of immunosuppressive approach in allo-HSCT for specific subgroups of non-malignant diseases requiring a reduced risk of toxicities, offering the opportunity to discuss the essential points for achieving patients\' long-term survival after MRD HSCT in BMF. Commentary on: Alsultan et al. Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia. Br J Haematol 2023;203:255-263.

When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti-thymocyte globulin (ATG) are frequently administered, but to-date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low-dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non-Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft-versus-host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2, two ANKRD26, two TINF2, one LZTFL1, one RTEL1 and one DNAJC21). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post-transplant, the event-free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low-dose Cy as part of a fludarabine-based regimen is safe and effective in SAA/non-Fanconi anaemia IBMFS.

Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by insufficient blood cell production and increased risk of transformation to myeloid malignancies. While genetically diverse, IBMFS are collectively defined by a cell-intrinsic hematopoietic stem cell (HSC) fitness defect that impairs HSC self-renewal and hematopoietic differentiation. In IBMFS, HSCs frequently acquire mutations that improve cell fitness, a phenomenon known as somatic compensation. Somatic compensation can occur via distinct genetic processes such as loss of the germline mutation or somatic alterations in pathways affected by the disease-causing gene. While the clinical implications of somatic compensation in IBMFS remain to be fully discovered, understanding these mutational processes can help understand disease pathophysiology and may inform future diagnostic and therapeutic approaches. In this review, we highlight current understanding about somatic compensation in IBMFS.

Somatic runt-related transcription factor 1 (RUNX1) mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Mono-allelic RUNX1 mutations in germline cells may cause familial platelet disorder (FPD), an inherited bone marrow failure syndrome (IBMFS) associated with an increased lifetime risk of AML. It is suspected that additional RUNX1 mutations may play a role in the pathogenesis of hematological malignancies in IBMFS. This review aims to study the role of RUNX1 mutations in the pathogenesis of hematological malignancies in patients with IBMFS. A PubMed database search was conducted using the following medical subject heading (MeSH) terms: \"inherited bone marrow failure syndromes,\" \"hematological neoplasms,\" \"gene expression regulation, leukemic,\" \"RUNX1 protein, human,\" \"RUNX1 protein, mouse,\" and \"Neutropenia, Severe Congenital, Autosomal recessive.\" Three studies published in 2020 were identified as meeting our inclusion and exclusion criteria. Leukemic progression in severe congenital neutropenia was used as a disease model to evaluate the clinical, molecular, and mechanistic basis of RUNX1 mutations identified in hematological malignancies. Studies in mice and genetically reprogrammed or induced pluripotent stem cells (iPSCs) have shown that isolated RUNX1 mutations are weakly leukemogenic and only initiate hyperproduction of immature hematopoietic cells when in combination with granulocyte colony-stimulating factor 3 receptor (GCSF3R) mutations. Despite this, whole-exome sequencing (WES) performed on leukemogenic transformed cells revealed that all AML cells had an additional mutation in the CXXC finger protein 4 (CXXC4) gene that caused hyperproduction of the ten-eleven translocation (TET2) protein. This protein causes inflammation in cells with RUNX1 mutations. This process is thought to be critical for clonal myeloid malignant transformation (CMMT) of leukemogenic cells. In conclusion, the combinations of GCSF3R and RUNX1 mutations have a prominent effect on myeloid differentiation resulting in the hyperproduction of myeloblasts. In other studies, it has been noted that the mutations in GCSF3R and RUNX1 genes are not sufficient for the full transformation of leukemogenic cells to AML, and an additional clonal mutation in the CXXC4 gene is essential for full transformation to occur. These data have implicitly demonstrated that RUNX1 mutations are critical in the pathogenesis of various hematological malignancies, and further investigations into the role of RUNX1 are paramount for the development of new cancer treatments.

Fanconi anemia, telomeropathies and ribosomopathies are members of the inherited bone marrow failure syndromes, rare genetic disorders that lead to failure of hematopoiesis, developmental abnormalities, and cancer predisposition. While each disorder is caused by different genetic defects in seemingly disparate processes of DNA repair, telomere maintenance, or ribosome biogenesis, they appear to lead to a common pathway characterized by premature senescence of hematopoietic stem cells. Here we review the experimental data on senescence and inflammation underlying marrow failure and malignant transformation. We conclude with a critical assessment of current and future therapies targeting these pathways in inherited bone marrow failure syndromes patients.