Evidence for reduced B-cell progenitors in early (low-risk) myelodysplastic syndrome

Sternberg, Alexander

doi:10.1182/blood-2005-04-1543

Cited by 127 publications

(93 citation statements)

References 58 publications

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“…27 Thus, overexpression of miR-127 may be linked with the downregulation of genes involved in B-cell lineage differentiation previously seen in MDS. 11,28 In CD34+ cells of all MDS subtypes, we confirmed an upregulation of the miR-1/miR-133a cluster (Po0.05, see Supplementary Table 2), which was recently published by Hussein et al 9 In contrast to increased expression in MDS/AML, this miRNA cluster was downregulated in neutrophils from patients with polycythemia vera and essential trombocytosis, 29 indicating its different roles in myeloid neoplasms. 5qÀ syndrome is a MDS subtype characterized by interstitial deletion of the long arm of chromosome 5.…”

Section: Discussionsupporting

confidence: 58%

Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome

et al. 2010

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MicroRNAs (miRNAs) are small non-coding RNAs functioning as regulators of hematopoiesis. Their differential expression patterns have been linked with various pathological processes originating from hematopoietic stem cells (HSCs). However, limited information is available regarding the role of miRNAs in myelodysplastic syndrome (MDS). Using miRNA arrays, we measured expression of 1,145 miRNAs in CD34+ bone marrow cells obtained from 39 MDS and acute myeloid leukemia (AML) evolved from MDS patients, and compared them with those of six healthy donors. Differential miRNA expression was analyzed and a panel of upregulated (n¼13) and downregulated (n¼9) miRNAs were found (Po0.001) in MDS/AML patients. An increased expression of a large miRNA cluster mapped within the 14q32 locus was detected. Differences in miRNA expression of MDS subtypes showed a distinction between early and advanced MDS; an apparent dissimilarity was observed between RAEB-1 and RAEB-2 subtypes. In early MDS, we monitored upregulation of proapoptotic miR-34a, which may contribute to the increased apoptosis of HSCs. Patients with 5q deletion were characterized by decreased levels of miR-143* and miR-378 mapped within the commonly deleted region at 5q32. This is an early report describing differential expression in MDS CD34+ cells, likely reflecting their disease-specific regulation.

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Section: Discussionsupporting

confidence: 58%

Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome

et al. 2010

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“…While previous studies have shown there to be a decreased progenitor B-cell pool in patients with MDS in comparison to age-matched healthy controls, this study is the first to show by multivariate analysis the prognostic value of B-cell progenitors in low risk MDS. 8,11 Establishing a negative association between the percentage of progenitor B cells and survival, our results stand in line with previously published data reporting a reduced number of progenitor B cells in MDS. 8,11 Whereas we hypothesize that a reduction in the number of progenitor B cells is associated with an immunosuppressive environment, the reasons for and the pathophysiological consequences of a reduced progenitor B-cell pool in MDS remain to be elucidated.…”

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confidence: 82%

Regulatory T cells and progenitor B cells are independent prognostic predictors in lower risk myelodysplastic syndromes

et al. 2015

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“…We have demonstrated that normal elderly (age 65 y and older) HSCs in the same xenotransplantation model are inherently biased toward myeloid differentiation and exhibit limited lymphoid differentiation potential compared with normal young (age 20-35 y) HSCs (30). Because MDS prevalence increases with age, it is possible that the bias of normal elderly HSCs away from lymphoid differentiation predisposes them to develop into MDS HSCs, which we have shown to exhibit even poorer generation of lymphoid progeny, a phenotype that has been described in human MDS patients (33). Low risk MDS HSC xenografts also generate reduced frequencies of GMPs, consistent with the hypothesis that MDS HSCs are not only the disease initiating cell in MDS but also suggests that lineage bias and the phenotype of ineffective hematopoiesis are largely cell intrinsic.…”

Section: Discussionmentioning

confidence: 91%

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

Pang

Pluvinage

Price

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

259

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Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.myelodysplasia | blood disorders | aging | monosomy 7 | cancer stem cell T he World Health Organization (WHO) defines myelodysplastic syndromes (MDS) as a heterogeneous group of related clonal diseases characterized by variable cytopenias due to ineffective hematopoiesis and increased risk of progression to acute myeloid leukemia (AML) (1-4). To date, functional and diagnostic evaluations of immature hematopoietic cells in MDS have predominantly relied on unpurified or partially purified bone marrow cells (most frequently CD34 + cells; reviewed in ref. 5), which have limited power to identify cell lineage specific alterations. We have taken advantage of the purification of highly enriched HSCs and committed myeloid progenitors (6-9) via fluorescence activated cell sorting (FACS) to characterize hematopoietic subsets in primary MDS patient bone marrow samples with the goal of increasing the understanding of MDS pathogenesis.Recent fluorescence in situ hybridization (FISH) and gene expression data from purified HSCs from 5q-MDS patients have suggested an HSC origin for MDS (10-13). HSCs from MDS patients (MDS HSCs) are relatively resistant to lenalidomide and decitabine treatment, because even patients with cytogenetic remission, as determined by FISH on peripheral blood cells, can maintain a significant MDS HSC burden (12, 13). Nevertheless, HSCs from MDS patients have not been shown to initiat...

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Evidence for reduced B-cell progenitors in early (low-risk) myelodysplastic syndrome

Cited by 127 publications

References 58 publications

Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome

Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome

Regulatory T cells and progenitor B cells are independent prognostic predictors in lower risk myelodysplastic syndromes

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

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