Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: apoptotic cells recovered from high-density fraction of bone marrow aspirates

Abstract

A higher percentage of apoptotic cells (apoptotic index or AI) is consistently found in bone marrow (BM) biopsies compared to BM aspirates of patients with myelodysplastic syndrome (MDS). Most studies have only investigated the low-density fraction (LDF) mononuclear cells from BM aspirates following density separation for AI determination. In the present study, both LDF and high-density fraction (HDF) cells for AI were examined by electron microscopy (EM) in 10 MDS patients and 4 healthy donors. Matched BM biopsies were subjected to AI detection by in situ end labeling (ISEL) of fragmented DNA. The results indicate that in LDF and HDF cells, AI is consistently higher in MDS patients (8.5% vs 1.5%, respectively; P = .039) compared to healthy donors (27% vs 4%, respectively; P = .004). The BM biopsy AI was also higher in MDS patients than in healthy donors (3+ vs 0+, respectively; P = .036). In addition, in MDS patients, more apoptotic cells were found in HDF cells than in LDF cells (27% vs 8.5%, respectively;P = .0001). All stages of maturation, ranging from blasts to terminally mature cells belonging to all 3 lineages, were represented in the dying cells in both compartments. Using EM, typical Pelger-Huett–type cells appeared to be apoptotic granulocytes. Both LDF and HDF cells should be examined for an accurate estimation of apoptotic cells because AI would be underestimated if only the LDF cells were studied. Ultrastructural studies consistently show a higher AI in BM biopsies compared to BM aspirates despite the correction factor of HDF cells provided by AI. This may represent the actual extant state, which could conceivably be due to a higher concentration of proapoptotic signals in the biopsies.

Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions–a review

“…Many studies have revealed that TNF‐α is a potent stimulus for RELA/NFKB1 activation. However, this action contrasts the high TNF‐α and the low RELA/NFKB1 expression levels of early MDS (Shetty et al , 2000). Thus, it was proposed that other molecules, especially adaptor proteins involved in “downstream” events, can interfere with the autocrine TNF‐α stimulation and can cause RELA/NFKB1 constitutive activation.…”

“…This event occurs especially in early MDS because of the disrupted interactions between the marrow stromal cell compartment, which provide signals that affect the growth and maintenance of the MDS clone, and the neoplastic cell population, which produce “commands” that affect the surrounding stromal cells (Stirewalt et al , 2007). Both these cell populations are targeted by intrinsic defects (Rajapaksa et al , 1996; Shetty et al , 2000; Campioni et al , 2005) and show enhanced sensitivity to inhibitory cytokines (Claessens et al , 2002).…”

Chronic relapsing remitting Sweet syndrome – a harbinger of myelodysplastic syndrome

“…The clinical course is variable, reflecting the diverse pathobiology of the disease, with some patients having a more chronic stable course and longer life expectancy while others present with aggressive disease that evolves rapidly into AML (Greenberg et al , ). The paradox seen with cytopenias and a hypercellular marrow is secondary to increased intramedullary apoptosis (Parker et al , ; Shetty et al , ). Immunological responses are being recognized as important not only in the initiation but also progression of MDS (Kordasti et al , , ).…”

The Role of U2AF1 Mutations in the Pathogenesis of Myelodysplastic Syndromes

“…See also Table S7. Raza et al, 1995aRaza et al, , 1995bShetty et al, 2000;Woll et al, 2014;Yoshida, 1993). However, these mice do not show dysplasia, nor do they develop MDS or AML.…”