Programmed cell death is an intrinsic feature of MDS progenitors, predominantly found in the cluster-forming cells
ABSTRACT Bone marrows (BM) of myelodysplastic syndrome (MDS) patients show increased proliferation and premature programmed cell death (PCD) in vivo as well as in vitro. We explored the proliferative capacity and apoptotic propensity of CD34+ progenitor cells of MDS patients excluding accessory cell interference.
CD34+/CD3-/CD19- cells of 5 MDS patients and 5 normal BM were sorted as single cells into single wells and were cultured in liquid medium. Wells were evaluated on days 4, 7, 10, and 14. PCD was determined by staining with annexin V-FITC. Growth rate and cell doubling time (Td) were calculated for each colony-forming cell.
Normal BM CD34+ cells formed clusters and colonies and both showed increasing PCD in time, although within colonies the degree of apoptosis was twice as high (about 25%) as compared with clusters at all time points. In MDS increased cluster formation was observed at all evaluation points when compared to normal BM, whereas the number of colonies was markedly reduced (1/7 of normal). These colonies were also smaller, usually smaller than 100 cells. Significantly enhanced levels of PCD of clusters (53-79%) in combination with longer cell doubling times explain this slower formation of smaller colonies. Surprisingly, these colonies showed considerably lower levels of PCD (7-32%) as compared to normal (1-48%, median values).
In the absence of stromal influences and accessory cells, this study in MDS patients showed intrinsically enhanced proliferation and apoptosis of cluster-forming cells, as the opposite was true for colony-forming cells.
Full-textDOI: · Available from: Lambert F R Span, Jan 15, 2014
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Article: Programmed cell death is an intrinsic feature of MDS progenitors, predominantly found in the cluster-forming cells
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ABSTRACT: Transformation of MDS into ALL during childhood is extremely rare. We report a rare case of an 8-yr-old girl who presented with refractory cytopenia of childhood (RCC) that transformed into ALL only 3 months after the diagnosis of childhood MDS. Although no cytogenetic abnormalities were observed in conventional karyotype and FISH analysis, we found several deletions on chromosomes 5q, 12q, 13q, and 22q. Partial homozygous deletion of the RB1 gene was observed on microarray analysis, with the bone marrow specimen diagnosed as ALL. This is the first case report of transformation of ALL from childhood MDS in Korea. We also compared the clinical, cytological, and cytogenetic features of 4 previously reported childhood MDS cases that transformed into ALL.Annals of Laboratory Medicine 03/2013; 33(2):130-135. DOI:10.3343/alm.2013.33.2.130 · 1.48 Impact Factor
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ABSTRACT: INTRODUCTION: Lower risk myelodysplastic syndromes (MDSs) are characterised by increased apoptosis of haematopoietic cells in the bone marrow (BM). The mechanism driving this excessive apoptosis involves multiple immune molecules, including inflammatory cytokines such as interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and interleukins (ILs). Interleukin-17(IL-17) is the hallmark cytokine produced by CD4+ Th17 cells, and IL-17 mediates activation of the adaptive T cell response, inducing an inflammatory cytokine environment. However, little is known about the role of IL-17 in MDS-associated immune dysfunction. METHODS: A total of 47 patients with myelodysplastic syndromes were enrolled in this study, and the levels of IL-17 and IL-17 receptor (IL-17R) in BM mononuclear cells (BMNCs) were detected by real-time polymerase chain reaction (RQ-PCR) and enzyme-linked immunosorbent assay (ELISA). Then, BMNCs were stimulated with recombinant human IL-17 (rhIL-17), and flow cytometry was used to analyse the production of IFN-γ and TNF-α by CD4+ and CD8+ T lymphocytes from lower risk MDS patients. Characterisation of IL-17 expression in patients with the HLA-DR15 allele or hypocellularity was also performed. RESULTS: mRNA levels for both IL-17 and the IL-17R subunits in BMNCs and for IL-17 in the BM and plasma were higher in patients with lower risk MDS as compared to patients with higher risk MDS and normal controls. The production of IFN-γ and TNF-α by CD4+ and CD8+ T lymphocytes from lower risk MDS patients could be enhanced by recombinant human IL-17 (rhIL-17) treatment. Furthermore, increased IL-17 expression was associated with more severe anaemia in MDS patients. CONCLUSION: Elevated IL-17 levels and IL-17-induced IFN-γ and TNF-α overproduction may be involved in the pathogenesis of lower risk MDS. © 2013 John Wiley & Sons A/S.European Journal Of Haematology 01/2013; 90(5). DOI:10.1111/ejh.12074 · 2.41 Impact Factor