The growth of myelodysplastic bone marrow in long-term cultures

Borbényi, Zita; Cinkotai, C; Harrison, Christine J.; Testa, NG

doi:10.1038/bjc.1987.56

Cited by 16 publications

(10 citation statements)

References 15 publications

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“…While deficiency in the growth and output of clonogenic cells has been previously shown to be greatly reduced in the majority of MDS bone marrow, no significant abnormalities in the stromal compartment have been demonstrated. [42][43][44] This defect and those seen in short-term hematopoietic colony cultures are consistent with our results, and have been interpreted as the consequence of the presence of inhibitory factors, decreased production or responsiveness to growth factors, or a defect in MDS accessory cells. 39,45 In contrast to these studies, our culture system used allogeneic stromal layers instead of autologous LTBMC.…”

Section: Discussionsupporting

confidence: 90%

Measurement of secondary colony formation after 5 weeks in long-term cultures in patients with myelodysplastic syndrome

et al. 1998

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Pancytopenia is a frequent manifestation of myelodysplastic syndromes (MDS). In the presence of an empty bone marrow, clinical distinction from aplastic anemia may be difficult. The hypoplastic marrow morphology seen in some cases of MDS raises questions about etiologic and pathophysiologic relationships between aplastic anemia and MDS. The goal of our study was to compare the degree of the hematopoietic failure in these diseases at the level of the most immature progenitor and stem cells that can be measured in vitro. In a systemic, prospective fashion, we have studied bone marrow (n = 45) and peripheral blood (n = 33) of patients with MDS for the number of long-term culture initiating cells (LTC-IC) in comparison to 17 normal controls and patients with new, untreated aplastic anemia (46 marrow; 62 blood samples). Due to the low numbers of cells available for the analysis, formal limiting dilution analysis could not be performed, instead secondary colony-forming cells (CFC) after 5 weeks of LTBMC were measured. As the number of these cells is proportional to the input number of LTC-IC, the number of secondary CFC per 10 6 mononuclear cells (MNC) initiating the LTBMC can be used as a measure of the content of immature stem cells in bone marrow and peripheral blood. The MDS group consisted of 34 RA, three RARS, eight RAEB and two RAEB-T patients with mean absolute neutrophil values of 1992, 1413, 1441, and 380 per mm 3 , respectively. The diagnosis was established based on bone marrow morphology and results of cytogenetic studies. In comparison to controls (147 ± 38/10 6 MNC), significantly decreased numbers of bone marrow secondary CFC were found in MDS: in patients with RA and RARS, 21 ± 7 secondary CFC per 10 6 bone marrow MNC (P Ͻ 0.001); patients with RAEB and RAEB-T: 39 ± 12 CFC per 10 6 marrow MNC (P Ͻ 0.001). In all groups tested, the decrease in peripheral blood secondary CFC numbers was consistently less pronounced. In MDS patients with hypocellular bone marrow, secondary CFC were lower but not significantly different in comparison to MDS with hypercellular marrow (18 ± 6 vs 35 ± 11; NS; hypoplastic bone marrow also was not associated with significantly lower neutrophil counts). However, in 24% of patients with MDS, bone marrow secondary CFC were within the normal range, while in the aplastic anemia group only one of the patients showed secondary CFC number within normal range. Bone marrow and blood secondary CFC numbers in hypoplastic RA were significantly higher than those in severe aplastic anemia 919 ± 5 in bone marrow, P Ͻ 0.01; 7 ± 2 in blood, P Ͻ 0.05). This trend was even more pronounced in hypoplastic RA with chromosomal abnormalities. However, no significant differences were found between the secondary CFC numbers in hypoplastic RA and moderate aplastic anemia. We concluded that, although the deficiency in the stem cell compartment is less severe in MDS than in aplastic anemia, depletion of early hematopoietic cells is an essential part of the pathophysiology in both diseases.

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Section: Discussionsupporting

confidence: 90%

Measurement of secondary colony formation after 5 weeks in long-term cultures in patients with myelodysplastic syndrome

et al. 1998

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“…Assessment of the function of marrow stromal cells can now be approached in vitro using LTBMC. The phenotypic abnormalities such as lack of confluence and fat cell formation of the adherent cell layers in LTBMC of some MDS patients, documented previously (Borbenyi et al, 1987) and in this study, are likely to reflect derangement in the composition and/or in the proliferative capacity of the stromal population. The only stromal cell precursor for which a clonal assay is available, the fibroblast colony forming cell (CFU-F).…”

Section: Discussionsupporting

confidence: 61%

Functional studies of bone marrow haemopoietic and stromal cells in the myelodysplastic syndrome (MDS)

et al. 1990

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Long-term bone marrow culture (LTBMC) was used to investigate the proliferative behaviour of marrow cells from a spectrum of cases of the myelodysplastic syndrome (MDS), and the results compared with those obtained in the conventional short-term clonal assay. Two broad patterns of growth were revealed in LTBMC. In one group the incidence of haemopoietic progenitor cells steadily declined to abnormally low levels at 4 weeks, while in a second group they were maintained near normal levels for periods of up to 7 weeks. These growth patterns, which were not predictable from clonogenic assays on the marrow cells prior to LTBMC, or from the morphology of the bone marrow, may reflect the stage of evolution of the disease. Further studies of clonality are required to establish whether or not patients exhibiting the second pattern have a potentiality to harbour residual normal haemopoiesis. LTBMC was also used to study the function of MDS marrow stroma in terms of its ability to sustain the growth of normal haemopoietic progenitor cells. Although the phenotype of the cultured adherent cell layer, obtained from some patients, was atypical, no consistent functional defect of MDS stroma could be identified by studying the level of haemopoiesis reached by normal cells seeded into MDS stroma.

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“…Long-term marrow cultures from patients with good-prognosis MDS subtypes tend to produce normal adherent layers, but in poor-prognosis subtypes incomplete stroma confluence with reduced fat cell formation has been observed [25,40]. Similar to the findings in AML and CML, the macrophage stroma compartment appears to be functionally abnormal.…”

Section: Stromal Abnormalities In Mdsmentioning

confidence: 57%

Stromal abnormalities in neoplastic bone marrow diseases

Dührsen

Hossfeld

1996

Annals of Hematology

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Bone marrow malignancies are clonal disorders resulting from neoplastic transformation of hematopoietic stem or progenitor cells. Similar to their normal counterparts, transformed blood-forming cells remain dependent on signals from the hematopoiesis-regulating stromal environment for survival and proliferation. There is increasing evidence that the microenvironment may also take a more active part in the disease process. A review of the literature on stromal abnormalities in the leukemias, the myelodysplastic syndromes, and multiple myeloma reveals three principal mechanisms by which stromal derangements can contribute to the evolution of a neoplastic disease. In the simplest case, neoplastic blood-forming cells induce reversible changes in stroma function or composition which result in improved growth conditions for the malignant cells ('malignancy-induced microenvironment'). In the second setting, functionally abnormal end cells derived from the malignant clone become an integral part of the stroma system, selectively stimulating the neoplastic cells and inhibiting normal blood cell formation ('malignant microenvironment'). In the third condition, the emergence of a neoplastic cell population is the consequence of a primary stroma lesion characterized by inability to control regular blood cell formation ('malignancy-inducing microenvironment'). The perception of different stroma-related disease mechanisms may eventually lead to the development of alternative therapeutic approaches.

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The growth of myelodysplastic bone marrow in long-term cultures

Cited by 16 publications

References 15 publications

Measurement of secondary colony formation after 5 weeks in long-term cultures in patients with myelodysplastic syndrome

Measurement of secondary colony formation after 5 weeks in long-term cultures in patients with myelodysplastic syndrome

Functional studies of bone marrow haemopoietic and stromal cells in the myelodysplastic syndrome (MDS)

Stromal abnormalities in neoplastic bone marrow diseases

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