Expression of the proliferation-associated nuclear protein MIB-1 and its relationship with microvascular density in bone marrow biopsies of patients with myelodysplastic syndromes

Abstract

The myelodysplastic syndromes (MDS) are a group of disorders characterized by dysplastic hemopoiesis and an increased risk of leukemic transformation. The process of angiogenesis has been implicated in the pathogenesis and evolution of MDS. In this study the proliferative activity and extent of angiogenesis was examined in bone marrow samples from 54 patients with MDS in relation to clinicopathologic features. Cellular proliferation and microvascular density (MVD) were examined immunohistochemically, using the monoclonal antibody MIB-1 (Ki-67) and an anti-CD34 monoclonal antibody respectively. Serum concentrations of interleukin-6 (IL-6) were measured by ELISA. The results showed that the MIB-1 Labeling Index (MIB-1 LI), MVD and IL-6 increased significantly with advancing severity of disease. Among the MDS-FAB subtypes, MIB-1 LI, MVD and IL-6 were significantly higher in RAEB-t, RAEB and CMML in comparison to RA and RARS (p < 0.0001 in all cases). Similarly, MIB-1 and MVD were increased in patients with score 3 in comparison to scores 0 and 1 in the IPSS system (p < 0.05). All parameters studied were significantly higher in patients versus controls. We conclude that cellular proliferative activity and angiogenesis are associated with disease progression in MDS patients.

Bone marrow cell cycle markers in inherited bone marrow failure syndromes

“…Our observations are in agreement with the published literature that indicates overexpression of p53 and Ki-67 in MDS/AML [5-7, 10, 16]; however, the close resemblance in overexpression of these markers between IBMFS and MDS/AML has not been reported previously. Similarities in the rate of overexpression of p53 and Ki-67 between IBMFS and MDS/AML may suggest a common cell cycle deregulation mechanism that is responsible for the preleukemic and leukemic processes in these marrow disorders.…”

“…Overexpression of p53 was also observed in low grade MDS (refractory anemia [RA]) when compared with acquired aplastic anemia [8], and in a proportion of AML and MDS marrows [9]. While some studies noted that the expression of Ki-67 was higher in high risk than low risk MDS, and in MDS than in normal controls [10], others found no difference in the expression of Ki-67 mRNA between AML, ALL and normal controls [11]. Survivin expression was increased in more than half of over 100 bone marrow aspirates from patients treated for de novo AML, while most of the remaining samples lacked any expression [12]; in another study, survivin expression was higher in the marrow of MDS and MDS-derived leukemia than normal controls [13].…”

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

“…The proliferative index of advanced MDS is uncertain, with some studies showing a decreased proliferative rate and others an increased proliferative rate, compared with early MDS. [52][53][54] Our data support a defect in regulation of the cell cycle in advanced MDS. The downregulation of several pathways involving the cell cycle in AML, including cell cycle regulation by BRCA1 and CDC25, has also recently been shown.…”

Chronic myelomonocytic leukemia: Forefront of the field in 2015

“…Likewise, Wimazal, et al found increased MVD and elevated levels of VEGF in the bone marrows of patients with CMML; immature myeloid cells were the source of VEGF [68]. Alexandrakis et al further confirmed the importance of angiogenesis in CMML by demonstrating increased MVD and increased levels of angiogenin and interleukin 6 in patients with CMML [69, 70]. Finally, Bellamy, et al proposed an autocrine function of VEGF, demonstrating that some patients’ CMML cells expressed cytoplasmic VEGF as well as the membranous VEGF receptors Flt-1 and KDR.…”