Bcl-xL prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin

Rhodes, Melissa; Kopsombut, Prapaporn; Bondurant, Maurice C.; Price, James O.; Koury, Mark J.

doi:10.1182/blood-2004-11-4344

Cited by 65 publications

(57 citation statements)

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“…Consistently, increased expression of two anti-apoptotic proteins, BCL-X L and MCL-1, 26,27 was observed in the bone marrow and spleen cell lysates prepared from mk/mk mice treated for 4 days with EPO when compared to untreated mk/mk mice ( Figure 2C). These data further confirm a positive effect of EPO on the survival of DMT1-mutant erythroid precursors.…”

Section: Erythropoietin Ameliorates Apoptosis In Mk/mk Erythroblastssupporting

confidence: 54%

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

et al. 2012

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BackgroundHypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be improved with high-dose erythropoietin supplementation. The aim of this study was to characterize and compare erythropoiesis in samples from a DMT1-mutant patient before and after treatment with erythropoietin, as well as in a mouse model with a DMT1 mutation, the mk/mk mice. Design and MethodsColony assays were used to compare the in vitro growth of pre-treatment and post-treatment erythroid progenitors in a DMT1-mutant patient. To enable a comparison with human data, high doses of erythropoietin were administered to mk/mk mice. The apoptotic status of erythroblasts, the expression of anti-apoptotic proteins, and the key components of the bone marrow-hepcidin axis were evaluated. ResultsErythropoietin therapy in vivo or the addition of a broad-spectrum caspase inhibitor in vitro significantly improved the growth of human DMT1-mutant erythroid progenitors. A decreased number of apoptotic erythroblasts was detected in the patient's bone marrow after erythropoietin treatment. In mk/mk mice, erythropoietin administration increased activation of signal transducer and activator of transcription 5 (STAT5) and reduced apoptosis in bone marrow and spleen erythroblasts. mk/mk mice propagated on the 129S6/SvEvTac background resembled DMT1-mutant patients in having increased plasma iron but differed by having functional iron deficiency after erythropoietin administration. Co-regulation of hepcidin and growth differentiation factor 15 (GDF15) levels was observed in mk/mk mice but not in the patient. ConclusionsErythropoietin inhibits apoptosis of DMT1-mutant erythroid progenitors and differentiating erythroblasts. Ineffective erythropoiesis associated with defective erythroid iron utilization due to DMT1 mutations has specific biological and clinical features.Key words: DMT1, apoptosis, ineffective erythropoiesis, erythropoietin.Citation: Horvathova M, Kapralova K, Zidova Z, Dolezal D, Pospisilova D, and Divoky V. Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts. Haematologica 2012;97(10):1480-1488. doi:10.3324/haematol.2011 This is an open-access paper.Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

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Section: Erythropoietin Ameliorates Apoptosis In Mk/mk Erythroblastssupporting

confidence: 54%

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

et al. 2012

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“…8). Among the 4 apoptosis-related proteins surveyed, the expression of Bax and Bcl-xL (known to mediate Epo's direct antiapoptotic action [28][29][30][31][32][33][34][35] ) were virtually identical in the paclitaxel-sensitive A2780 and the relatively paclitaxel resistant A2780 2m35U cells. However, expression of both Bcl-2 and Bcl-10 was substantially lower in the A2780 2m35U cells, and paclitaxel treatment may have reduced these levels further.…”

Section: Long-term Epo Treated Paclitaxel-resistant A2780 2m35u Cellsmentioning

confidence: 99%

Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel‐resistant phenotype

Solár

Feldman

Jeong

et al. 2007

Intl Journal of Cancer

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Erythropoietin (Epo), a glycoprotein hormone that is the principal regulator of erythropoiesis, is known to act also on nonhematopoietic cell types. Epo receptors have been reported on several normal and neoplastic human cells and tissues, including ovarian cancer cells. We found that long-term Epo treatment of A2780 cells resulted in the development of a phenotype exhibiting both enhanced Epo signaling, evidenced by increased peak levels of phospho-Erk1/2 and increased paclitaxel resistance. This phenotypic effect was specific for paclitaxel, since no change in cisplatin or carboplatin sensitivity was observed. In addition, the change in phenotype was stable, even after the removal of Epo. Measurement of mono-and oligonucleosome formation revealed that longterm Epo treated A2780 cells exhibited markedly less apoptosis than nonerythropoietin treated cells at essentially all concentrations of paclitaxel tested. Western blot analyses revealed that the long-term Epo treated cells had significantly reduced expression of apoptosis-related proteins Bcl-2 and Bcl-10. These findings may have implications for the clinical use of recombinant human Epo and other erythropoiesis stimulating agents to correct anemia in paclitaxel-treated cancer patients. ' 2007 Wiley-Liss, Inc.Key words: erythropoietin; signaling; ovarian cancer; paclitaxel; chemoresistance; apoptosis Erythropoietin (Epo) is the prime regulator of erythroid cell growth and differentiation. Additionally, a wide variety of normal and malignant nonhematopoietic cells have been reported to express the Epo receptor (EpoR) and in some cases, Epo has been shown to act on these cells, sometimes as a survival/antiapoptotic factor (reviewed in Ref. 1).Reports of erythropoietin receptor (EpoR) expression by a variety of cancer cell types and the use of recombinant human erythropoietin (epoetin) and darbepoetin to treat anemia in cancer patients have raised concern regarding the potential for antiapoptotic effects of these erythropoiesis stimulating agents on the cancer itself. [2][3][4][5][6] Some clinical studies have proven especially worrisome. The Breast Cancer Erythropoietin Trial (BEST) was terminated early because of increased mortality in patients receiving Epo. 6 There was an increase in early disease progression. A trial of Epo in head and neck cancer patients treated with radiotherapy resulted in an increase in locoregional recurrence and a decrease in survival in the Epo-treated group. 5 Recently, a trial of darbepoetin to enhance radiosensitivity of head and neck cancer was stopped due to a significantly poorer outcome in the darbepoetin treatment group. 7,8 In an accompanying study, we show that each of 4 human ovarian cancer cell lines, including A2780, expresses both the EpoR and Epo at the mRNA and protein levels. Additionally, we show that these EpoR are functional in initiating Epo-dependent intracellular signaling and that an Epo/EpoR autocrine/ paracrine mechanism may be operative in enhancing ovarian cancer cell growth.In the present report, we ha...

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“…The responsiveness of erythroblasts to EPO is diminished during their maturation due to a decrease in EPO-R expression, and therefore mature erythroblasts are no longer dependent on EPO (Wickrema et al, 1992). However, several in vitro studies using murine erythroblasts demonstrated that Bcl-xL might act later in maturation, on cells that are actively producing hemoglobin, rather than on immature cells (Motoyama et al, 1999;Rhodes et al, 2005). These studies suggest that in murine erythropoiesis Bcl-xL contributes to prevention of apoptosis in late-stage erythroblasts that are no longer EPO-dependent.…”

Section: Introductionmentioning

confidence: 93%

“…Moreover, these results from rat erythroblasts are coincident with the observations of murine erythroblasts. Several in vitro studies using murine erythroblasts have demonstrated that the Bcl-xL-deficient latestage erythroblasts underwent apoptosis (Motoyama et al, 1999;Rhodes et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…These studies suggest that in murine erythropoiesis Bcl-xL contributes to prevention of apoptosis in late-stage erythroblasts that are no longer EPO-dependent. On the other hand, Mcl-1 is a possible candidate for the anti-apoptotic effect of EPO in early-stage erythroblasts prior to hemoglobin synthesis in bcl-x -/-mice (Gregoli and Bondurant, 1997;Rhodes et al, 2005). Moreover, Mcl-1 is known to prevent apoptosis of human chronic myeloid leukemia cell lines in an EPO-dependent manner (Fukuchi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Bcl-xL and Mcl-1 are involved in prevention of in vitro apoptosis in rat late-stage erythroblasts derived from bone marrow

et al. 2012

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-Apoptosis controls erythroid homeostasis by balancing survival and death of erythroid cells. The mitochondrial pathway of apoptosis involves regulation of apoptotic events caused by the Bcl-2 family proteins, including the anti-apoptotic and pro-apoptotic members. However, little has been reported on the role of the anti-apoptotic Bcl-2 family members in rat late-stage erythroblasts that are no longer erythropoietin (EPO)-dependent. In the present study, to investigate this we analyzed changes in apoptosis-related factors that occurred in vitro. EPO stimulation resulted in reduced apoptotic cell death of the late-stage erythroblasts accompanied by decreased caspase-3 and caspase-9 activities, which is indicative of the induction of apoptosis through the mitochondrial pathway. Analysis of mRNA expression of the Bcl-2 family proteins demonstrated that EPO stimulation up-regulated the Bcl-xL mRNA, resulting in decreases in the mRNA ratios of Bak, Bax, and Bad to Bcl-xL. Also, the mRNA ratios of Bak and Noxa to Mcl-1 were decreased, mainly due to up-regulation of Mcl-1 mRNA. These results showed a close association between reduced apoptotic cell death and increased mRNA levels of Bcl-xL and Mcl-1 in the presence of EPO. Thus, the present study suggests that Bcl-xL may be an important anti-apoptotic factor of rat late-stage erythroblasts as has been reported in murine erythroblasts. Moreover, the results also indicate the possibility that Mcl-1 may act on the rat late-stage erythroblasts as an anti-apoptotic factor.

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Bcl-xL prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin

Cited by 65 publications

References 34 publications

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel‐resistant phenotype

Bcl-xL and Mcl-1 are involved in prevention of in vitro apoptosis in rat late-stage erythroblasts derived from bone marrow

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