Expression of the proliferating cell nuclear antigen in bone marrow cells from patients with myelodysplastic syndromes and aplastic anemia

doi:10.1016/0046-8177(93)90082-R

Human Pathology

Volume 24, Issue 4, April 1993, Pages 359-363

https://doi.org/10.1016/0046-8177(93)90082-R Get rights and content

Abstract

To determine the proliferative activity of the hematopoietic cells under nonneoplastic and/or neoplastic conditions, the expression of a cell cycle-related antigen, the proliferating cell nuclear antigen (PCNA), was examined in the bone marrow trephines of 79 individuals, 12 of whom had no hematologic disorder, 32 of whom had a diagnosis of myelodysplastic syndromes (MDSs), 20 of whom suffered from aplastic anemia, and 15 of whom had a diagnosis of acute myeloid leukemia. Most of the patients with MDS had more than 15% PCNA-positive cells (23.5% ± 1.5%) while patients with no hematologic disorder showed fewer than 15% PCNA-positive cells (11.7% ± 0.7%). The overall ratio of the PCNA-positive cell fraction in the bone marrow was considered of prognostic value for predicting transition into overt leukemia from MDS. Aplastic anemia cases usually exhibited hypocellular bone marrow and an infrequent labeling with the anti-PCNA antibody (3.5% ± 0.5%). However, a few aplastic anemia cases showed hypercellular bone marrow and a significantly high PCNA-positive cell ratio (32.0% ± 4.4%). In the bone marrow of acute myeloid leukemia patients more than 20% of total nucleated cells were positive for PCNA (30.0% ± 2.2%). The results suggest that the expression of PCNA is associated with the regulation of bone marrow cell proliferation and the bone marrow cellularity, and that these findings would serve as an early indicator of evolution of overt leukemia in MDS and also would be useful in distinguishing MDS cases from aplastic anemia cases when the bone marrow is hypocellular or normocellular.

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Cited by (30)

Overexpression of MCM2 in myelodysplastic syndromes: Association with bone marrow cell apoptosis and peripheral cytopenia
2012, Experimental and Molecular Pathology
Citation Excerpt :
Myelodysplastic syndromes (MDS) constitute a heterogeneous group of hematological malignancies, characterized by morphological dysplasia, impaired differentiation, defective cellular function, genetic instability, and ineffective hematopoiesis (Bennett, 2005; Mufti, 2004). Among these features, ineffective hematopoiesis is mainly caused by the proliferation and simultaneous frequent apoptosis of bone marrow hematopoietic cells (Fontenay-Roupie et al., 1999; Kitagawa et al., 1992, 1997, 1998, 1999; Parcharidou et al., 1999) and, as a result, MDS cases exhibit peripheral blood cytopenia despite bone marrow hypercellularity. Excessive apoptosis was mediated by a number of pro-apoptotic factors, including pro-inflammatory cytokines that were overexpressed in the MDS bone marrow (Corey et al., 2007).
Myelodysplastic syndromes (MDS) are characterized by proliferation and apoptosis of bone marrow cells. Minichromosome maintenance protein (MCM) 2, which is known to be essential for regulating DNA replication, has proven to have a pro-apoptotic effect in our recent study. Thus, to determine the role of MCM2 in MDS, real-time PCR, immunohistochemistry and in vitro analysis were performed. Our results showed higher MCM2 expression in MDS than in control and AML. Notably, there was no correlation between MCM2 and Ki67-labeling indices (LIs) in MDS, while MCM2 LIs were significantly correlated with cleaved caspase 3 LIs in MDS. In vitro analysis revealed that MCM2 overexpression induced apoptosis in HL60 cells. Furthermore, MDS bone marrow exhibited higher ratio of MCM2 and cleaved caspase 3 double-positive cells and the ratio was correlated with the degree of leukocytopenia. These results suggest that the up-regulated expression of MCM2 is associated with frequent apoptosis in MDS and may have an important role in the pathogenesis of MDS.
Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia
2004, Leukemia Research
Bone marrow cells of patients with myelodysplastic syndromes (MDS) frequently undergo apoptosis, though the apoptotic cell ratio decreases when overt leukemia (OL) develops. Thus, we compared the expression of the inhibitor of apoptosis protein (IAP) gene family proteins in bone marrow samples from control, MDS, OL transformed from MDS (MDS → OL), and de novo acute myelogenous leukemia (AML) subjects by the quantitative real-time RT-PCR method and an immunohistochemical approach. Overexpression of mRNA for survivin, cIAP1, NAIP and XIAP was significant in MDS bone marrow cells compared with control samples. However, the expression of mRNA for survivin, cIAP1 and cIAP2 exhibited a remarkable decrease after the development of OL (MDS → OL). By immunohistochemistry, survivin was found to localize to the nucleus of myeloid cells in the majority of MDS cases. Next, the chronological changes in the expression of IAPs were determined in cases of MDS with evolution of OL. Although the expression of cIAP1 and cIAP2 revealed a sudden or gradual decrease as OL developed, survivin in many cases and XIAP in the majority of cases exhibited a peak of expression before a decline, indicating that these IAPs could be associated with the early events in the development of OL.
Proliferating cell nuclear antigen (PCNA) expression of megakaryocytopoiesis in normal human bone marrow and reactive lesions with special emphasis on HIV-myelopathy
1994, Pathology Research and Practice
A morphometric analysis was performed on bone marrow trephine biopsies using sequential double-immunostaining, to evaluate endoreduplicative activity of megakaryocytopoiesis. A total of 104 marrow specimens were studied with employment of monoclonal antibodies PC1 0 (anti-proliferating cell nuclear antigen - PCNA) and Y21S.1-CD61 (anti-platelet glycoprotein IIIa). In addition to the control group patients included non-specific inflammatory changes, HI V-myelopathy with normal or decreased platelet counts, idiopathic thrombocytopenic purpura (ITP), and finally reactive thrombocytosis (TH). To exclude an undue overexpression of PCNA, in a comparative pilot study we also applied MIB1 (KI-67 antigen) on normal bone marrow specimens. In accordance with the various modalities of cell-cycle marker expression, no significantly different findings were disclosed. PCNA-labelling index was relatively low, ranging from 0.8 to 1.7 % of the total megakaryocytopoiesis (promegakaryoblasts to mature plateletshedding megakaryocytes). A significant relationship between megakaryocyte size and PCNA-expression was determinable. This implies that some of the cases with a prevalence of small megakaryocytes, like ITP, have the tendency to show a higher proportion of positively-stained cells. Moreover, this feature confirms a hypothesis postulating a decrease in the time for DNA-synthesis (S-phase) and a relative prolongation of the Gel G2-phases of the cell-cycle at higher ploidy levels (large-sized megakaryocytes). On the other hand, it may be speculated that some of the hyperpolyplold giant megakaryocytes may have reached their endstage of endoreduplication and enter into Go-phase. In comparison with the control group and the other entities under study, a significant reduction of PCNA-reactivity was recognizable in HIV-myelopathy accompanied by' thrombocytopenia. Our findings are in keeping with cell culture studies assuming that, opposed to ITP and TH, in AIDS different kinetic properties of the megakaryocytic lineage have to be encountered. In this context, it may not entirely be ruled out that viral infection has an inhibitory effect on the stability of mRNA for PCNA and therefore could cause an undue reduction of PCNA-immunostaining.
Bone marrow niches in myeloid neoplasms
2020, Pathology International
Differential expression of ACINUS variants in bone marrow in myelodysplastic syndromes
2017, International Journal of Clinical and Experimental Pathology
Over-expression of cancerous inhibitor of PP2A (CIP2A) in bone marrow cells from patients with a group of high-risk myelodysplastic syndromes
2014, Pathology and Oncology Research

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^☆: Supported in part by a grant-in-aid for scientific research (no. 02770183) from the Ministry of Education, Science, and Culture of Japan.

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Human Pathology

Abstract

References (27)

Cyclin (PCNA, auxiliary protein of DNA polymerase delta) is a central component of the pathway(s) leading to DNA replication and cell division

FEBS Lett

Synthesis of the nuclear protein cyclin (PCNA) and its relationship with DNA replication

Exp Cell Res

Mutation of Ki-ras and N-ras oncogenes in myelodysplastic syndromes

Blood

The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing

Blood

Regulation of the proliferating cell nuclear antigen cyclin and thymidine kinase mRNA levels by growth factors

J Biol Chem

Proliferating cell nuclear antigen expression in childhood acute leukemia

Blood

Direct relationship between remission duration in acute myeloid leukemia and cell cycle kinetics: A leukemia intergroup study

Blood

Growth fractions in malignant non-Hodgkin's lymphoma (NHL) as determined in situ with the monoclonal antibody Ki-67

Hematol Oncol

Expression of nuclear antigen p145 in bone marrow cells of patients with myeloid leukemia

Cancer Res

Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: An index of cell proliferation with evidence of deregulated expression in some neoplasms

J Pathol

DNA content and cell cycle analysis of bone marrow cells in myelodysplastic syndromes (MDS)

Br J Haematol

Proliferative activity of bone marrow cells in primary dysmyelopoietic (preleukemic) syndromes

Cancer

Proposals for the classification of the myelodysplastic syndromes

Br J Haematol

Cited by (30)

Overexpression of MCM2 in myelodysplastic syndromes: Association with bone marrow cell apoptosis and peripheral cytopenia

Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia

Proliferating cell nuclear antigen (PCNA) expression of megakaryocytopoiesis in normal human bone marrow and reactive lesions with special emphasis on HIV-myelopathy

Bone marrow niches in myeloid neoplasms

Differential expression of ACINUS variants in bone marrow in myelodysplastic syndromes

Over-expression of cancerous inhibitor of PP2A (CIP2A) in bone marrow cells from patients with a group of high-risk myelodysplastic syndromes

Original contributionExpression of the proliferating cell nuclear antigen in bone marrow cells from patients with myelodysplastic syndromes and aplastic anemia☆

Abstract

FEBS Lett

Exp Cell Res

Blood

Blood

J Biol Chem

Blood

Blood

Growth fractions in malignant non-Hodgkin's lymphoma (NHL) as determined in situ with the monoclonal antibody Ki-67

Hematol Oncol

Expression of nuclear antigen p145 in bone marrow cells of patients with myeloid leukemia

Cancer Res

Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: An index of cell proliferation with evidence of deregulated expression in some neoplasms

J Pathol

DNA content and cell cycle analysis of bone marrow cells in myelodysplastic syndromes (MDS)

Br J Haematol

Proliferative activity of bone marrow cells in primary dysmyelopoietic (preleukemic) syndromes

Cancer

Proposals for the classification of the myelodysplastic syndromes

Br J Haematol

Original contribution
Expression of the proliferating cell nuclear antigen in bone marrow cells from patients with myelodysplastic syndromes and aplastic anemia☆