Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

Brzeźniakiewicz‐Janus, Katarzyna; Rupa‐Matysek, Joanna; Gil, Lidia

doi:10.1007/s12015-020-09971-y

Cited by 10 publications

(15 citation statements)

References 116 publications

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“…Hereditary AA occurs by gene defects and is usually diagnosed in childhood; Moreover, this form of AA is rare compared to the acquired. Most acquired cases are triggered by environmental exposure to toxins, drugs, radiation, and viral infections in addition to its potential idiopathic causes (Brzeźniakiewicz‐Janus et al, 2020). Generally, the underlying pathophysiology for initiation and pathology of acquired AA is believed to be immune‐mediated T cells that cause the destruction of HSCs.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cell‐derived extracellular vesicles conditionally ameliorate bone marrow failure symptoms in an immune‐mediated aplastic anemia mouse model

Gholampour

Abroun

Nieuwland

et al. 2021

Journal Cellular Physiology

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Acquired forms of Aplastic anemia (AA) are characterized by T cell‐mediated immune disease resulting in bone marrow (BM) failure and marrow hypoplasia. In these cases, it is a major challenge to modulate autoreactive T cell activity and thereby decrease the pro‐inflammatory cytokine storm. Emerging evidence indicates that extracellular vesicles derived from mesenchymal stem cells (MSC‐EVs) control and modulate immunity. The therapeutic potential of MSC‐EVs has not been investigated in acquired AA. Hence, in this study, we constructed an AA mice model through irradiation and splenocyte infusion to test the benefits of hypoxic MSC‐EVs (Hx‐EVs) and normoxic MSC‐EVs (Nx‐EVs). We found that MSC‐EVs treatment significantly prolonged the survival rate and increased the platelet (PLT) counts of the AA mice. Immunohistochemical staining and colony assay confirmed amelioration of hypoplasia in the BM and increased numbers of hematopoietic stem cells (HSCs). These effects of MSC‐EVs were mediated by T cell suppression and inhibition of interferon‐gamma (IFN‐γ) and tumor necrosis factor‐alpha (TNF‐α) production in the AA mouse model. In addition, an in vitro study revealed that MSC‐EVs led to reduced IFN‐γ and TNF‐α levels and there was an association with decreased splenocyte viability. Previous studies examined the diagnostic and prognostic values of microRNAs (miRNAs) in AA and identified miR‐199a, miR‐146a, miR‐223, and miR‐126. We used quantitative real‐time PCR to evaluate the expression of these miRNAs on isolated BM mononuclear cells (BM‐MNCs) from treated and untreated AA mice. miR‐223, miR‐146a, and miR‐199a expressions increased in the MSC‐EVs treated AA mice. Treatment with MSC‐EVs increased expression of miR‐223 and miR‐146a. Our findings showed that treatment with MSC‐EVs significantly ameliorated immune destruction of HSCs in the AA mouse model and confirmed the importance of miRNAs in the clinical status of this model.

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Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cell‐derived extracellular vesicles conditionally ameliorate bone marrow failure symptoms in an immune‐mediated aplastic anemia mouse model

Gholampour

Abroun

Nieuwland

et al. 2021

Journal Cellular Physiology

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“…Genotypic variants of the DNA repair gene, X-ray cross complementary group 3 ( XRCC3 ) have been associated with a significantly higher cancer risk including AML ( Bănescu et al, 2013 ), whereas polymorphisms of NAT2 an acetylator with epigenetic influences have been described as a modifier of tumorigenesis in various solid tumors (; Zhu et al, 2021 ). In addition, WES allowed identification of a pathogenic TERC mutation in a patient previously affected by AA ( Young, 2018 ; Brzeźniakiewicz-Janus et al, 2020 ). In this contest, the evolution to AML was accompanied by the acquisition of RUNX1 mutations.…”

Section: Discussionmentioning

confidence: 99%

Molecular Profiling of Kenyan Acute Myeloid Leukemia Patients

et al. 2022

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Acute myeloid leukemia (AML) is an infrequent disease, and it is associated with high morbidity and mortality. It harbors a unique configuration of cytogenetic abnormalities and molecular mutations that can be detected using microscopic and molecular methods respectively. These genetic tests are core elements of diagnosis and prognostication in high-income countries. They are routinely incorporated in clinical decision making, allowing for the individualization of therapy. However, these tests are largely inaccessible to most patients in Kenya and therefore no data has been reported on this group of patients. The main purpose of this study is to describe the cytogenetic and molecular abnormalities of acute myeloid leukemia patients seen at the hemato-oncology unit of Kenyatta National Hospital. A cross-sectional descriptive study was carried out over a 3-month period on ten patients with a diagnosis of AML. Social demographics and clinical data were collected through a study proforma. A peripheral blood sample was collected for conventional metaphase G-banding technique and next generation sequencing. Particularly, targeted DNA sequencing (Illumina myeloid panel) and whole exome sequencing (WES) were performed. Cytogenetic analysis failed in 10/10 cases. Targeted sequencing was successfully obtained in 8 cases, whereas WES in 7. Cytogenetic studies yielded no results. There were 20 mutations detected across 10 commonly mutated genes. All patients had at least one clinically relevant mutation. Based on ELN criteria, NGS identified three patients with high-risk mutations, affecting TP53 (n = 2) and RUNX1 (n = 1). One patient was classified as favorable (PML-RARA) while 4 were standard risk. However, WT1 mutations associated with unfavorable prognosis were recorded in additional 2 cases. WES showed concordant results with targeted sequencing while unveiling more mutations that warrant further attention. In conclusion, we provide the first molecular profiling study of AML patients in Kenya including application of advanced next generation sequencing technologies, highlighting current limitations of AML diagnostics and treatment while confirming the relevance of NGS in AML characterization.

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“…Approximately 10%–15% of patients with severe aplastic anemia (SAA) experience leukemic transformation following IST, and in some patients, this transformation emerges during or shortly after IST ( 19 – 23 ). Such a short interval that spans the transformation process indicates that leukemic clones preexist in the SAA stage ( 24 – 27 ) and rapidly expand due to depletion of cytotoxic T lymphocytes (CTLs) or the induction of immune tolerance ( 28 – 32 ) rather than due to the acquisition of novel molecular events. In patients with genetic aberrations typically observed in MNs, there is a greater frequency of transformation to MNs.…”

Section: Reciprocal Transformations Between Aa and Mnsmentioning

confidence: 99%

“…Currently, AA is also known to be a clonal hematological disease. Clonal HPCs gain a selective proliferative and survival advantage over their normal counterparts in a chronic inflammatory setting and become the dominant hematopoietic components ( 24 – 27 ). Moreover, some patients with MDS or AML can present heavily reduced BM cellularity at initial diagnosis or during disease progression, and patients with low-risk MDS have an immunological landscape similar to that of SAA ( 39 – 43 ).…”

Section: Clonal Hematopoiesis In Aamentioning

confidence: 99%

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

Zhao,

Ju,

Xiu

et al. 2024

Front. Immunol.

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Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%–15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

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Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

Cited by 10 publications

References 116 publications

Mesenchymal stem cell‐derived extracellular vesicles conditionally ameliorate bone marrow failure symptoms in an immune‐mediated aplastic anemia mouse model

Mesenchymal stem cell‐derived extracellular vesicles conditionally ameliorate bone marrow failure symptoms in an immune‐mediated aplastic anemia mouse model

Molecular Profiling of Kenyan Acute Myeloid Leukemia Patients

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

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