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PurposeDeficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2.MethodsWe conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS).ResultsThirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT.ConclusionHCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency.Clinical ImplicationsHCT is a definitive cure for DADA2 with > 95% survival.

Pediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.

Bone marrow failure (BMF) syndromes are a heterogenous group of non-malignant hematologic diseases characterized by single- or multi-lineage cytopenia(s) with either inherited or acquired pathogenesis. Aberrant T or B cells or innate immune responses are variously involved in the pathophysiology of BMF, and hematological improvement after standard immunosuppressive or anti-complement therapies is the main indirect evidence of the central role of the immune system in BMF development. As part of this immune derangement, pro-inflammatory cytokines play an important role in shaping the immune responses and in sustaining inflammation during marrow failure. In this review, we summarize current knowledge of cytokine signatures in BMF syndromes.

Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of disorders characterized by defective hematopoiesis, impaired stem cell function, and cancer susceptibility. Diagnosis of IBMFS presents a major challenge due to the large variety of associated phenotypes, and novel, clinically relevant biomarkers are urgently needed. Our study identified nuclear interaction partner of ALK (NIPA) as an IBMFS gene, as it is significantly downregulated in a distinct subset of myelodysplastic syndrome-type (MDS-type) refractory cytopenia in children. Mechanistically, we showed that NIPA is major player in the Fanconi anemia (FA) pathway, which binds FANCD2 and regulates its nuclear abundance, making it essential for a functional DNA repair/FA/BRCA pathway. In a knockout mouse model, Nipa deficiency led to major cell-intrinsic defects, including a premature aging phenotype, with accumulation of DNA damage in hematopoietic stem cells (HSCs). Induction of replication stress triggered a reduction in and functional decline of murine HSCs, resulting in complete bone marrow failure and death of the knockout mice with 100% penetrance. Taken together, the results of our study add NIPA to the short list of FA-associated proteins, thereby highlighting its potential as a diagnostic marker and/or possible target in diseases characterized by hematopoietic failure.

U2AF1 is involved in the recognition of the 3′ splice site during pre-mRNA splicing. Mutations in U2AF1 are frequently observed in myelodysplastic syndromes. However, the role of wild-type U2AF1 in normal hematopoiesis has remained elusive. Using a novel conditional U2af1 knockout allele, we have found that deletion of U2af1 results in profound defects in hematopoiesis characterized by pancytopenia, ablation of hematopoietic stem/progenitor cells (HSPC) leading to bone marrow failure and early lethality in mice. U2af1 deletion impairs HSPC function and repopulation capacity. U2af1 deletion also causes increased DNA damage and reduced survival in hematopoietic progenitors. RNA sequencing analysis reveals significant alterations in the expression of genes related to HSC maintenance, cell proliferation, and DNA damage response-related pathways in U2af1-deficient HSPC. U2af1 deficiency also induces splicing alterations in genes important for HSPC function. This includes altered splicing and perturbed expression of Nfya and Pbx1 transcription factors in U2af1-deficient HSPC. Collectively, these results suggest an important role for U2af1 in the maintenance and function of HSPC in normal hematopoiesis. A better understanding of the normal function of U2AF1 in hematopoiesis is important for development of appropriate therapeutic approaches for U2AF1 mutant induced hematologic malignancies.

Inherited bone marrow failure syndromes are genetic hematologic disorders with increased cancer risk. Accurate diagnosis is crucial for appropriate management. This study assessed the clinical usefulness of next-generation sequencing (NGS)-based target gene sequencing in pediatric and AYA (adolescent and young adult) patients with hematologic abnormalities. From December 2019 to June 2023, 93 patients with suspected congenital hematologic diseases at a single institution underwent NGS-based testing. Medical records were retrospectively reviewed. The median age at diagnosis was 9.3 years (range 0.2–31.4), with 59.1% males. Indications for testing included specific medical histories (28 patients), persistent cytopenia or recurrent neutropenic fever (22 patients), changes in cytopenia patterns (11 patients), and other reasons (32 patients). Pathogenic variants were identified in 9/28 (32.1%), 3/22 (13.6%), 4/11 (36.4%), and 0/32 (0%). Overall, 16 patients (17.2%) had pathogenic variants, including FANCA , BRCA2 , PMS2 , ELANE , G6PC3 and VPS13B in patients with idiopathic neutropenia, and GATA2 in patients with suspected myelodysplastic syndrome. Genetic findings led to diagnostic revisions in 12 patients (12.9%), including reclassification of aplastic anemia (AA) as Fanconi anemia, Diamond-Blackfan anemia, or Shwachman-Diamond syndrome, prompting hematopoietic stem cell transplantation and altering cancer surveillance. Pathogenic variants were more frequently observed in patients with a specific medical history or changes in cytopenia, and in those with additional clinical features (cytogenetic abnormalities or non-severe AA). This study demonstrated the diagnostic usefulness of NGS-based target gene sequencing for pediatric and AYA patients with suspected genetic hematologic disorders, supporting the need for multicenter studies and standardized guideline development.

MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development.

Inherited Bone Marrow Failure Syndromes (IBMFS) encompass a group of rare genetic disorders characterized by intrinsic hematopoietic stem cell defects, leading to impaired hematopoiesis and increased predisposition to malignancies, particularly hematologic cancers. As advances in supportive care and hematopoietic stem cell transplantation have extended patient survival, there is growing recognition of an elevated risk of solid tumors, including colorectal cancer (CRC), within this population. Epidemiologic data, although limited by small cohort sizes, suggest the need for earlier and more intensive CRC surveillance protocols tailored to IBMFS patients, who tend to develop CRC at younger ages compared to the general population. Among IBMFS, the most robust association with CRC has been reported in Diamond–Blackfan anemia syndrome (DBAS) and Fanconi anemia (FA), while emerging evidence suggests a potential link in dyskeratosis congenita (DC) and Shwachman–Diamond syndrome (SDS). The pathophysiological basis involves defective DNA repair mechanisms, telomere dysfunction, ribosomal protein abnormalities, and impaired cellular stress responses, each contributing to genomic instability and malignant transformation. The understanding of the molecular mechanisms underpinning the association between IBMFS and CRC may provide a foundation for future targeted prevention and surveillance strategies and offer broader insights into colorectal carcinogenesis.

Severe aplastic anemia (SAA) is an acquired, T cell-driven bone marrow (BM) failure disease characterized by elevated interferon gamma (IFNγ), loss of hematopoietic stem cells (HSCs), and altered BM microenvironment, including dysfunctional macrophages (MΦs). T lymphocytes are therapeutic targets for treating SAA, however, the underlying mechanisms driving SAA development and how innate immune cells contribute to disease remain poorly understood. In a murine model of SAA, increased beta-chemokines correlated with disease and were partially dependent on IFNγ. IFNγ was required for increased expression of the chemokine receptor CCR5 on MΦs. CCR5 antagonism in murine SAA improved survival, correlating with increased platelets and significantly increased platelet-biased CD41 hi HSCs. T cells are key drivers of disease, however, T cell-specific CCR5 expression and T cell-derived CCL5 were not necessary for disease. CCR5 antagonism reduced BM MΦs and diminished their expression of Tnf and Ccl5 , correlating with reduced frequencies of IFNγ-secreting BM T cells. Mechanistically, CCR5 was intrinsically required for maintaining BM MΦs during SAA. Ccr5 expression was significantly increased in MΦs from aged mice and humans, relative to young counterparts. Our data identify CCR5 signaling as a key axis promoting the development of IFNγ-dependent BM failure, particularly relevant in aging where Ccr5 expression is elevated.

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance. The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. Here the authors demonstrate that hematopoietic stem cells with short telomeres induced by mutations affecting telomerase complex genes undergo differentiation towards megakaryopoiesis through the activation of the IFI16-mediated interferon response.