CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins

Sloand, Elaine M.; Pfannes, Loretta; Chen, Gubin; Shah, Simant; Solomou, Elena E.; Barrett, John; Young, Neal S.

doi:10.1182/blood-2006-01-030643

Cited by 96 publications

(68 citation statements)

References 33 publications

(30 reference statements)

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“…These cells expressed increased [10]. The findings in previous research that trisomy 8+cells are Fas+ and annexin V+ is consistent with a cell population under immune attack and undergoing apoptosis [12]. This was postulated to be due to an immune response directed against neoantigens on trisomy 8+ cells.…”

Section: Discussionsupporting

confidence: 63%

“…New DNA hypomethylating agents azacytidine and decitabine have shown efficacy in patients with high-risk MDS and they may delay the disease progression [1]. Novel therapeutic strategies include molecular inhibition of MDS stem cell apoptosis as well as trials to use small-interfering-RNA to knock down survivin [12]. …”

Section: Discussionmentioning

confidence: 99%

“…In trisomy 8+ MDS, patients suffer predominantly from pancytopenia, and the diagnosis can be confounded by aplastic anaemia since some cases of aplastic anaemia can evolve into trisomy 8+ MDS [12], in which 8+ appears to confer a favourable prognosis [13]. Chromosomal defects, as grouped by IPSS, and blast cell percentages are so far the most relevant parameters for predicting overall survival and progression-free intervals in MDS [14].…”

Section: Introductionmentioning

confidence: 99%

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Growth advantage of CD34+ cells in trisomy 8 highrisk myelodysplastic syndrome despite enhanced apoptotic signals

Youssef¹,

Ismail²,

Wahed³

et al. 2012

Easter Mediterr Health J

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This study examined haematopoietic stem cells of 19 high-risk cases of myelodysplastic syndrome (MDS) for apoptotic and anti-apoptotic signals and cellular proliferation and correlated these with clinical and cytogenetic subtypes, particularly trisomy 8. The aim was to identify cellular and cytogenetic markers of prognostic relevance to survival of high-risk MDS cases. High-risk MDS cases had a significantly higher percentage of apoptotic CD34+ cells and anti-apoptotic survivin+ cells than controls, particularly for trisomy 8 cases. Trisomy 8+ cells showed a significant positive correlation with apoptotic CD34+ cells and capacity for colony formation. The latter was significantly lower in trisomy-8-negative cases than normal controls, while that of trisomy 8 cases was comparable to controls. Our results suggest that although trisomy 8 cells are in a pro-apoptotic state, they are checked by the enhanced expression of anti-apoptotic signals which provide them with their proliferative advantage.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Growth advantage of CD34+ cells in trisomy 8 highrisk myelodysplastic syndrome despite enhanced apoptotic signals

Youssef¹,

Ismail²,

Wahed³

et al. 2012

Easter Mediterr Health J

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“…Notably, this chromosomal abnormality is commonly associated with clonal evolution in FA (39,40), and it might be involved in the attenuation mechanism. It is noteworthy that the molecular target and related downstream pathways of gross chromosomal abnormalities in neoplasias remain largely to be identified, see for instance trisomy 8 or monosomy 7 in clonal evolution of aplastic anemia or MDS/AML in non-FA patients (41)(42)(43)(44). Finally, it is likely that other changes in pathways that regulate cellular stress, apoptosis, and senescence can also contribute to cell survival and transformation throughout the natural history of FA patients, as occurs in mice (45).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous abrogation of the G2 DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients

Ceccaldi¹,

Briot²,

Larghero³

et al. 2011

J. Clin. Invest.

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DNA damage checkpoints in the cell cycle may be important barriers against cancer progression in human cells. Fanconi anemia (FA) is an inherited DNA instability disorder that is associated with bone marrow failure and a strong predisposition to cancer. Although FA cells experience constitutive chromosomal breaks, cell cycle arrest at the G 2 DNA damage checkpoint, and an excess of cell death, some patients do become clinically stable, and the mechanisms underlying this, other than spontaneous reversion of the disease-causing mutation, are not well understood. Here we have defined a clonal phenotype, termed attenuation, in which FA patients acquire an abrogation of the G 2 checkpoint arrest. Attenuated cells expressed lower levels of CHK1 (also known as CHEK1) and p53. The attenuation could be recapitulated by modulating the ATR/CHK1 pathway, and CHK1 inhibition protected FA cells from cell death. FA patients who expressed the attenuated phenotype had mild bone marrow deficiency and reached adulthood, but several of them eventually developed myelodysplasia or leukemia. Better understanding of attenuation might help predict a patient's clinical course and guide choice of treatment. Our results also highlight the importance of evaluating the cellular DNA damage checkpoint and repair pathways in cancer therapies in general.

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“…upregulated genes in patients with trisomy 8 were primarily involved in immune and inflammatory responses. 74,77 All patients had significant CD8+ T-cell expansions of one or more T-cell receptor vß subfamilies. These findings are consistent with an immune response where activated T cells, in proximity to trisomy 8 cells which would express neoantigen, would release cytokines up-regulating Fas expression on the surface of hematopoietic cells.…”

Section: Trisomymentioning

confidence: 99%

Prognostic Implications of Cytogenetic Features in Myelodysplastic Syndromes

Belli¹,

Bestach²,

Kornblihtt³

et al. 2013

Oncology &Amp; Hematology Review (US)

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Myelodysplastic Syndromes (MDS) are a heterogeneous group of hematologic diseases characterized by refractory cytopenia(s) and variable risk of leukemic progression. Cytogenetic analysis is important in day-to-day clinical practice helping to define subgroups of MDS patients who share similarities in the course of the disease. There are recurring aberrations affecting chromosomes 5, 7, 8, and 20. While all of them do not suggest a therapeutic approach, their presence has been considered as a risk indicator since the original international prognostic scoring system (IPSS) was published. The most recent cytogenetic stratifications tried to find the prognostic significance of less frequent alterations which have been longer included in the intermediate group. Moreover, monitoring of karyotype changes is suggested to evaluate cytogenetic response to treatments and the acquisition of new aberrations associated to an unfavorable outcome. This review focuses on different cytogenetic risk stratifications that have been published during the past 20 years and the molecular background of the most relevant chromosomal findings.

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CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins

Cited by 96 publications

References 33 publications

Growth advantage of CD34+ cells in trisomy 8 highrisk myelodysplastic syndrome despite enhanced apoptotic signals

Growth advantage of CD34+ cells in trisomy 8 highrisk myelodysplastic syndrome despite enhanced apoptotic signals

Spontaneous abrogation of the G2 DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients

Prognostic Implications of Cytogenetic Features in Myelodysplastic Syndromes

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