title: Erythroid progenitors from patients with low-risk myelodysplastic syndromes are dependent on the surrounding micro environment for their survival.
abstract: To investigate whether the type of programmed cell death of myelodysplastic erythroid cells depends on their cellular context, we performed studies on cells from patients with low-risk myelodysplastic syndromes. We compared erythroid cells (and their precursor cells) from the mononuclear cell fraction with those from the hematon fraction, which are compacted complexes of hematopoietic cells surrounded by their own micro-environment. In directly fixed materials, erythroblasts exhibited signs of autophagy with limited apoptosis (<3%) based on ultrastructural characteristics and immunogold labeling for activated caspase-3. After 24 h in culture, myelodysplastic erythroblasts exhibited a significant increase in apoptosis (22 ± 7% vs. 3 ± 2%, p = 0.001). In contrast, the myelodysplastic erythroblasts from the hematon fraction did not exhibit an increased tendency toward apoptosis after culture (7 ± 3.3% vs. 1.8 ± 2.3%), which was in line with results for normal bone marrow cells. The same dependency on the micro-environment was noted for immature erythroid progenitor cells. Myelodysplastic hematons exhibited distinct numbers of erythroid burst-forming units in association with an extensive network of stromal cells, whereas small numbers of erythroid burst-forming units were generated from the myelodysplastic mononuclear cells compared with normal mononuclear cells (10.2 ± 9 vs. 162 ± 125, p < 0.001). Co-culture of erythroid myelodysplastic cells in the presence of growth factors (vascular endothelial growth factor, leukemia inhibitory factor) or on the MS-5 stromal layer did not restore the expansion of erythroid precursor cells. These data indicate that surviving myelodysplastic erythroid progenitors become more vulnerable to programmed cell death when they are detached from their own micro-environment.
authors.affiliation: Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Folkerts
authors.affiliation: Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Carin L E
authors.initials: CL
authors.lastname: Hazenberg
authors.affiliation: Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Houwerzijl
authors.affiliation: Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Fiona A J
authors.initials: FA
authors.lastname: van den Heuvel
authors.affiliation: Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: André B
authors.initials: AB
authors.lastname: Mulder
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Johannes J L
authors.initials: JJ
authors.lastname: van der Want
authors.affiliation: Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: e.vellenga@umcg.nl.
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000473:pathology / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D059016:Tumor Microenvironment