Myelodysplastic syndromes

Li, Huan; Hu, Fang; Gale, Robert Peter; Sekeres, Mikkael A.; Liang, Yang

doi:10.1038/s41572-022-00402-5

Cited by 30 publications

(35 citation statements)

References 279 publications

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“…Myelodysplastic syndromes (MDS) represent a heterogeneous group of malignant and clonal diseases that originate from hematopoietic stem cells (HSCs) (Li et al, 2022; Raskovalova et al, 2020). The main features of MDS are bone marrow (BM) dysplasia and ineffective hematopoiesis, hallmarked by myeloid cell development abnormalities (Xing et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the current study was performed to evaluate the roles of BM MΦs from different clinical stages of MDS in regulating normal and malignant hematopoiesis (Li et al, 2022). The quantities of standard monocyte subsets, polarized M1/M2 and MΦ functions in patients with lower‐risk MDS, higher‐risk MDS, de novo AML, and healthy donors (HDs) were identified.…”

Section: Introductionmentioning

confidence: 99%

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Bone marrow macrophages are involved in the ineffective hematopoiesis of myelodysplastic syndromes

Xing,

Yao,

Zhao

et al. 2024

Journal Cellular Physiology

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Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective hematopoiesis. Accumulating evidence has shown that macrophages (MΦs) are important components in the regulation of tumor progression and hematopoietic stem cells (HSCs). However, the roles of bone marrow (BM) MΦs in regulating normal and malignant hematopoiesis in different clinical stages of MDS are largely unknown. Age‐paired patients with lower‐risk MDS (N = 15), higher‐risk MDS (N = 15), de novo acute myeloid leukemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. Flow cytometry analysis showed increased pro‐inflammatory monocyte subsets and a decreased classically activated (M1) MΦs/alternatively activated (M2) MΦs ratio in the BM of patients with higher‐risk MDS compared to lower‐risk MDS. BM MФs from patients with higher‐risk MDS and AML showed impaired phagocytosis activity but increased migration compared with lower‐risk MDS group. AML BM MΦs showed markedly higher S100A8/A9 levels than lower‐risk MDS BM MΦs. More importantly, coculture experiments suggested that the HSC supporting abilities of BM MΦs from patients with higher‐risk MDS decreased, whereas the malignant cell supporting abilities increased compared with lower‐risk MDS. Gene Ontology enrichment comparing BM MΦs from lower‐risk MDS and higher‐risk MDS for genes was involved in hematopoiesis‐ and immunity‐related pathways. Our results suggest that BM MΦs are involved in ineffective hematopoiesis in patients with MDS, which indicates that repairing aberrant BM MΦs may represent a promising therapeutic approach for patients with MDS.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bone marrow macrophages are involved in the ineffective hematopoiesis of myelodysplastic syndromes

Xing,

Yao,

Zhao

et al. 2024

Journal Cellular Physiology

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“…2 Diagnosis of MDS primarily relies on the presence of cytopenia, morphological evidence of dysplasia in bone marrow aspirate and biopsy, and clonal cytogenetic abnormalities. 1,3,4 However, MDS cases vary in clinical presentation, with some exhibiting atypical features, including inapparent or absent cytopenia and dysplasia, upon examination. 5,6 Diagnostic discrepancies may occur in 12% of patients at the time of initial presentation, affecting therapeutic decision-making.…”

Section: Introductionmentioning

confidence: 99%

“…The clinical presentation is nonspecific and includes symptoms and signs of thrombocytopenia, anemia, and neutropenia 2 . Diagnosis of MDS primarily relies on the presence of cytopenia, morphological evidence of dysplasia in bone marrow aspirate and biopsy, and clonal cytogenetic abnormalities 1,3,4 . However, MDS cases vary in clinical presentation, with some exhibiting atypical features, including inapparent or absent cytopenia and dysplasia, upon examination 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Construction and experimental validation of a novel ferroptosis‐related gene signature for myelodysplastic syndromes

Zhu,

He,

Wei

et al. 2024

Immunity Inflam & Disease

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BackgroundMyelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by morphological abnormalities and peripheral blood cytopenias, carrying a risk of progression to acute myeloid leukemia. Although ferroptosis is a promising target for MDS treatment, the specific roles of ferroptosis‐related genes (FRGs) in MDS diagnosis have not been elucidated.MethodsMDS‐related microarray data were obtained from the Gene Expression Omnibus database. A comprehensive analysis of FRG expression levels in patients with MDS and controls was conducted, followed by the use of multiple machine learning methods to establish prediction models. The predictive ability of the optimal model was evaluated using nomogram analysis and an external data set. Functional analysis was applied to explore the underlying mechanisms. The mRNA levels of the model genes were verified in MDS clinical samples by quantitative real‐time polymerase chain reaction (qRT‐PCR).ResultsThe extreme gradient boosting model demonstrated the best performance, leading to the identification of a panel of six signature genes: SREBF1, PTPN6, PARP9, MAP3K11, MDM4, and EZH2. Receiver operating characteristic curves indicated that the model exhibited high accuracy in predicting MDS diagnosis, with area under the curve values of 0.989 and 0.962 for the training and validation cohorts, respectively. Functional analysis revealed significant associations between these genes and the infiltrating immune cells. The expression levels of these genes were successfully verified in MDS clinical samples.ConclusionOur study is the first to identify a novel model using FRGs to predict the risk of developing MDS. FRGs may be implicated in MDS pathogenesis through immune‐related pathways. These findings highlight the intricate correlation between ferroptosis and MDS, offering insights that may aid in identifying potential therapeutic targets for this debilitating disorder.

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“…In recent years, there have been significant inroads made in the understanding of MDS with increased application of genomic sequencing. There are over 50 genes recurrently mutated in MDS, and these somatic mutations are apparent in up to 80% of patients with MDS, including those previously found to have a normal karyotype by conventional cytogenetic analysis (22). Despite that, the functional significance of many of the different mutations and how they interact to influence the disease phenotype and clinical outcomes remains to be resolved.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated expression ofHoxa1isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes

Tan

Joseph

Chalk

et al. 2023

Preprint

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The homeobox gene, Hoxa1, has two different isoforms generated by alternative splicing: a full-length homeodomain-containing Hoxa1 (Hoxa1-FL), and a truncated Hoxa1 (Hoxa1-T), that lacks the homeodomain. Oncoretroviral overexpression of wildtype Hoxa1 cDNA (WT-Hoxa1), which generates both Hoxa1 isoforms, in murine hematopoietic stem and progenitor cells (HSPCs) perturbed hematopoiesis, resulting in myelodysplastic syndromes (MDS) in mice. Overexpression of a mutated Hoxa1 cDNA (MUT-Hoxa1) that generates Hoxa1-FL but not Hoxa1-T led to a more severe MDS capable of transforming to secondary acute myeloid leukemia (sAML). Similar to human MDS, DNA damage repair pathways were downregulated in Hoxa1-overexpressing hematopoietic progenitor cells. Conditional knock-in mouse models revealed a Hoxa1-FL dosage-dependent effect on MDS disease severity. Our data reveal that increased expression of Hoxa1-FL in HSPCs is sufficient to initiate MDS in mice. CD34+ cells from up to 50% of patients with MDS had elevated HOXA1-FL expression, highlighting the clinical relevance of our mouse models.

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Myelodysplastic syndromes

Cited by 30 publications

References 279 publications

Bone marrow macrophages are involved in the ineffective hematopoiesis of myelodysplastic syndromes

Bone marrow macrophages are involved in the ineffective hematopoiesis of myelodysplastic syndromes

Construction and experimental validation of a novel ferroptosis‐related gene signature for myelodysplastic syndromes

Dysregulated expression ofHoxa1isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes

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