Aplastic Anemia as a Roadmap for Bone Marrow Failure: An Overview and a Clinical Workflow

Solimando, Antonio Giovanni; Palumbo, Carmen; Pragnell, Mary Victoria; Bittrich, Max; Argentiero, Antonella; Krebs, Markus

doi:10.3390/ijms231911765

Cited by 6 publications

(8 citation statements)

References 121 publications

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“…Nonetheless, to our knowledge, the present research represents the first report of the p.Cys174Arg STAT1 GOF variant in a patient with an inborn error of immunity developing aplastic anemia. A case-based study of patients with rare primary immunodeficiency demonstrates how careful investigations may provide pathophysiologic insights and suggest potential therapies for aplastic anemia and inborn immune errors that may be more broadly applicable [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

STAT1 overexpression triggers aplastic anemia: a pilot study unravelling novel pathogenetic insights in bone marrow failure

et al. 2023

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We identified STAT1 gain of function (GOF) in a 32-year-old female with pallor, weakness, cough, and dyspnea admitted to our Division of Medicine. She had severe oral ulcers (OU), type 1 diabetes (T1DM), and pancytopenia. Bone marrow (BM) biopsy showed the absence of erythroid precursors. Peripheral blood parameters such as neutrophils < 500/mL, reticulocytes < 2%, and BM hypo-cellularity allowed to diagnose severe aplastic anemia. A heterozygous variant (p.520T>C, p.Cys174Arg) of STAT1 was uncovered. Thus, p.Cys174Arg mutation was investigated as potentially responsible for the patient's inborn immunity error and aplastic anemia. Although STAT1 GOF is rare, aplastic anemia is a more common condition; therefore, we explored STAT1 functional role in the pathobiology of BM failure. Interestingly, in a cohort of six patients with idiopathic aplastic anemia, enhanced phospho-STAT1 levels were observed on BM immunostaining. Next, the most remarkable features associated with STAT1 signaling dysregulation were examined: in both pure red cell aplasia and aplastic anemia, CD8+ T cell genetic variants and mutations display enhanced signaling activities related to the JAK-STAT pathway. Inborn errors of immunity may represent a paradigmatic condition to unravel crucial pathobiological mechanisms shared by common pathological conditions. Findings from our case-based approach and the phenotype correspondence to idiopathic aplastic anemia cases prompt further statistically powered prospective studies aiming to elucidate the exact role and theragnostic window for JAK/STAT targeting in this clinical context. Nonetheless, we demonstrate how a comprehensive study of patients with primary immunodeficiencies can lead to pathophysiologic insights and potential therapeutic approaches within a broader spectrum of aplastic anemia cases.

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Section: Discussionmentioning

confidence: 99%

STAT1 overexpression triggers aplastic anemia: a pilot study unravelling novel pathogenetic insights in bone marrow failure

et al. 2023

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“…Another potential translational application is the use of our molecules for FA diagnosis. While FA should be suspected and searched for in all patients who develop bone marrow failure, only a fraction of them will be confirmed to have FA, the others having immunological aplastic anemia or other inherited causes ( 59 , 60 ). FA diagnosis is typically suspected in childhood when cytopenia occurs or based on typical malformations such as thumb abnormalities, but some individuals may not be diagnosed with FA until adulthood.…”

Section: Discussionmentioning

confidence: 99%

A clickable melphalan for monitoring DNA interstrand crosslink accumulation and detecting ICL repair defects in Fanconi anemia patient cells

Berrada

Martínez‐Balsalobre

Larcher

et al. 2023

Nucleic Acids Research

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Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA interstrand crosslinks (ICLs). In this study, we have developed and characterized a new tool to investigate ICL repair: a clickable version of the crosslinking agent melphalan which we name click-melphalan. Our results demonstrate that click-melphalan is as effective as its unmodified counterpart in generating ICLs and associated toxicity. The lesions induced by click-melphalan can be detected in cells by post-labelling with a fluorescent reporter and quantified using flow cytometry. Since click-melphalan induces both ICLs and monoadducts, we generated click-mono-melphalan, which only induces monoadducts, in order to distinguish between the two types of DNA repair. By using both molecules, we show that FANCD2 knock-out cells are deficient in removing click-melphalan-induced lesions. We also found that these cells display a delay in repairing click-mono-melphalan-induced monoadducts. Our data further revealed that the presence of unrepaired ICLs inhibits monoadduct repair. Finally, our study demonstrates that these clickable molecules can differentiate intrinsic DNA repair deficiencies in primary FA patient cells from those in primary xeroderma pigmentosum patient cells. As such, these molecules may have potential for developing diagnostic tests.

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“…Molecular analysis revealed the presence of somatic mutations in CBL (2.8%) , KMT2D (37.6%) and NF1 (44.6%), consistent with the mutations detected when the patient was initially diagnosed with MDS-EB-2, but the VAFs were slightly decreased. These morphological, immunological, and cytogenetic analyses favored a diagnosis of SAA[ 4 - 6 ], but the presence of myeloid neoplasm-associated somatic mutations and the medical history suggested a diagnosis of hMDS[ 1 , 2 , 9 , 10 ].…”

Section: Case Presentationmentioning

confidence: 99%

“…Aplastic anemia (AA) is a disease of hematopoietic failure caused by cellular immune-mediated destructive impairment of hematopoietic progenitor cells. Decreased hematopoietic volume and deranged autoimmunity are the underlying pathophysiology in AA development and diagnosis[ 4 - 6 ]. AA is generally considered a benign hematological disorder.…”

Section: Introductionmentioning

confidence: 99%

Flared inflammatory episode transforms advanced myelodysplastic syndrome into aplastic pancytopenia: A case report and literature review

Ju¹,

Xiu²,

Xu³

et al. 2023

World J Clin Cases

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BACKGROUND Myelodysplastic syndrome (MDS) is a hematological neoplasm, and an increase in myeloblasts is representative of leukemic hematopoiesis in advanced MDS. Low-risk MDS usually exhibits deranged autoimmunity resembling that of aplastic anemia (AA), whereas advanced MDS is characterized by a phenotype of immune exhaustion. MDS can be normo/hyperplastic or hypoplastic. Generally, bone marrow cellularity and myeloblasts increase with disease progression. Transformation from advanced MDS to AA-like syndrome with leukemic cell regression has not previously been reported. CASE SUMMARY A middle-aged Chinese woman had a 4-year history of leukocytopenia. Six months prior to admission, the patient developed gradually worsening fatigue and performance status. The leukocytopenia further progressed. She was diagnosed with MDS with excess blasts-2 based on increased bone marrow cellularity and an increased percentage of myeloblasts on marrow and blood smears, an increased percentage of cluster of differentiation (CD)34+CD33+ progenitors in immunotyping analysis, a normal karyotype in cytogenetic analysis, and the identification of somatic mutations in CBL, KMT2D and NF1 in molecular analysis. Initially, neutropenia was the predominant hematological abnormality, with mild anemia and thrombocytosis, and the degree of fatigue was far more severe than the degree of anemia. In the following months, the patient experienced several febrile episodes. Intravenous antibiotic treatments were able to control the febrile episodes, but the elevated inflammatory indices persisted. The hematological parameters dramatically fluctuated with the waxing and waning of the inflammatory episodes. With recurrent flares of the inflammatory condition, agranulocytosis and severe anemia developed, with mild thrombocytopenia. During the patient’s hospitalization, computed tomography (CT) scans revealed the presence of extensive inflammatory lesions involving the lungs, mediastinum, pleura, gastrointestinal tract, peritoneum and urinary tract, with imaging features suggestive of the reactivation of disseminated tuberculosis. Reevaluation of the bone marrow smears revealed that the cellularity became hypoplastic, and the leukemic cells regressed, suggesting that both normal and leukemic hematopoiesis had been heavily suppressed. Immunological analysis of the bone marrow samples revealed a decreased percentage of CD34+ cells and an immunological signature resembling that of severe AA (SAA), confirming the regression of the leukemic cells by autoimmune-mediated attacks. The patient demonstrated resistance to multiple drugs, including antituberculotics, recombinant human granulocyte colony-stimulating factor, broad-spectrum antibiotics, voriconazole, ganciclovir, immune suppressants, eltrombopag and intravenous immunoglobulin, which further worsened the hematological injury and patient’s performance status. The patient eventually died of overwhelming i...

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Aplastic Anemia as a Roadmap for Bone Marrow Failure: An Overview and a Clinical Workflow

Cited by 6 publications

References 121 publications

STAT1 overexpression triggers aplastic anemia: a pilot study unravelling novel pathogenetic insights in bone marrow failure

STAT1 overexpression triggers aplastic anemia: a pilot study unravelling novel pathogenetic insights in bone marrow failure

A clickable melphalan for monitoring DNA interstrand crosslink accumulation and detecting ICL repair defects in Fanconi anemia patient cells

Flared inflammatory episode transforms advanced myelodysplastic syndrome into aplastic pancytopenia: A case report and literature review

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