Hematopoietic turnover index in reactive and neoplastic bone marrow lesions: quantification by apoptosis and PCNA labeling

Abstract

In order to determine the dynamics of hematopoietic cell turnover, proliferative activity and incidence of apoptosis (programmed cell death) were evaluated in bone marrow trephine biopsies. Selection of patients (20 in each group) included in addition to a control group, idiopathic thrombocytopenia (ITP), reactive thrombocytosis (TH), secondary polycythemia-smokers' polyglobuly (PG), primary (essential-hemorrhagic) thrombocythemia (PTH), polycythemia vera (PV), and finally acute myeloid leukemia (AML). Apoptosis was demonstrated by the in situ end-labeling technique (ISEL) and proliferative activity by applying the monoclonal antibody PC10 raised against proliferating cell nuclear antigen (PCNA). To assess dynamic features of hematopoiesis, an index was calculated consisting of the ratio between PCNA-positive nuclei and the apoptotic cell fraction. This factor was termed the hematopoietic turnover index (HTI). Morphometric analysis revealed that the HTI was significantly increased in AML and PV. According to cell culture studies both disorders are characterized by either a prevalent proliferation of the myeloid or erythroid cell mass. On the other hand, PG, PTH, and TH showed no relevant enhancement of this index in comparison to the control specimen. In vitro experiment results are in keeping with the finding that PG and PTH are not associated with a significant expansion of the erythroid lineage (CFU-E). Similar to ITP and TH, in PTH megakaryocyte proliferation (CFU-MEG) is the predominant feature of cell turnover. Differences between PTH and TH are in line with the reduced in vitro formation of CFU-MEG in the latter disorder. In conclusion, our in situ study on turnover rates of the bone marrow in various neoplastic and reactive lesions extends previous experimental data on hematopoietic cell kinetics.

Prognostic impact of apoptosis and proliferation in idiopathic (primary) myelofibrosis

“…In early and advanced stages of disease, significant differences in the dynamics of hematopoiesis were found. In line with other MPDs [40], in early stages of IMF an imbalance between proliferation of cells and apoptosis was observable. The conspicuous increase in bone marrow cellularity is caused by the expanding (clonally transformed) myeloid cell mass in these cases.…”

“…Since changes of bone marrow morphology in IMF reflect a dynamic and stage-like process which is accompanied by a wellknown spectrum of clinical and hematological findings [11,16,21], corresponding alterations of the dynamics of hematopoiesis might be expected in various stages of disease. In view of findings derived from other MPDs [40], an imbalance between proliferation and cell death (apoptosis) has to be expected, particularly in early (hypercellular) stages of IMF which are characterized by an increase in bone marrow cellularity. Given the heterogeneity of survival patterns even in these early stages which may be accompanied by myeloid metaplasia [21], a better understanding of hematopoietic cell kinetics would substantially improve prognostic efficiency and stratification of patient subgroups.…”

The assessment of proliferating cell nuclear antigen (PCNA) immunostaining in myelodysplastic syndromes and its prognostic significance

“…According to cell kinetic studies, a prevalent cell production rate is detectable in the myeloblastic compartment and this in vitro finding is reflected by a significant increase in the PCNA labeling index (Allen 1993, Thiele 1996,Thiele 1997.The accumulation of the PCNA mRNA in cells followed by the synthesis of high levels of the protein is stimulated by growth factors, and as reported in a previous study, PCNA levels in leukemia reflect the activity of other growth regulatory genes that are associated with cell proliferation (Keim 1990, Kitagawa 1993.…”

Quantitative assessment of apoptotic and proliferative gingival keratinocytes in oral and sulcular epithelium in patients with gingivitis and periodontitis

“…1991) and it is also possible that a few TUNEL‐positive cells in this area have become necrotic after exposure to bacterial endotoxin and leukotoxin. To obtain an objective value of the cell turnover in all areas measured, we divided TUNEL values by the corresponding PC10 values (Thiele et al. 1997).…”