Dysregulated Human Myeloid Nuclear Differentiation Antigen Expression in Myelodysplastic Syndromes: Evidence for a Role in Apoptosis

Abstract

Reduced levels of human myeloid nuclear differentiation antigen (MNDA) gene transcripts have been detected in both familial and sporadic cases of myelodysplastic syndromes (MDS). Numerous reports implicate elevated apoptosis/ programmed cell death and death ligands and their receptors in the pathogenesis of MDS. MNDA and related proteins contain the pyrin domain that functions in signaling associated with programmed cell death and inflammation. We tested the hypothesis that MNDA is involved in the regulation of programmed cell death in human myeloid hematopoietic cells. Clones of K562 cells (MNDA-null) that expressed ectopic MNDA protein were established using retroviral transduction. MNDA-expressing K562 clones were resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, but were not protected from programmed cell death induced with genotoxic agents or H 2 O 2 . MNDA protein expression assessed in control and intermediate and high-grade MDS marrows showed several patterns of aberrant reduced MNDA. These variable patterns of dysregulated MNDA expression may relate to the variable pathophysiology of MDS. We propose that MNDA has a role regulating programmed cell death in myeloid progenitor cells, and that its down-regulation in MDS is related to granulocytemacrophage progenitor cell sensitivity to TRAIL-induced programmed cell death.

Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II

“…Transcription regulators ELL2, TLE3, and BCoR also up-regulated by TGF-␤ were implicated in the maintenance of undifferentiated cell states and in suppression of apoptosis (49 -51). Transcription factors that belong to the group of late TGF-␤ response genes in M2 macrophages include another AP-1 family member, FOS (27), and human myeloid nuclear differentiation Ag implicated in inflammatory reactions and apoptosis and present in macrophages in atherosclerotic plaques (52,53). We conclude that these transcription factors together with the R-Smads are responsible for the development of the macrophage phenotype observed after stimulation of M2 IL-4/GC by TGF-␤.…”

Evaluation of flow cytometric assessment of myeloid nuclear differentiation antigen expression as a diagnostic marker for myelodysplastic syndromes in a series of 269 patients

“…It has been detected in myelomonocytic precursors, monocytes, macrophages, subsets of normal B cells, AML blasts with maturation and certain B cell lymphomas, but not in other BM cells or nonhematopoietic cells, acute lymphatic leukemias, biphenotypic leukemias, AML without maturation and lymphatic blast crisis of chronic myeloid leukemia (23,26,(41)(42)(43)(44). Because both protein and gene expression of MNDA have been found at lower levels in patients with MDS (25,27,28) and given the availability of an MNDA-antibody applicable in MFC, the examination of MNDA expression by MFC is considered a potential discriminator between patients with MDS and those with other causes for cytopenias and healthy individuals. McClintock-Treep et al (29) compared the BM of 20 MDS patients with BM of 19 healthy controls, suggesting there were significant differences in the percentage of myeloid precursor cells with low MNDA expression in the MDS cohort.…”

“…It is capable of DNA binding and mediating protein-protein interaction, thereby slowing down proliferation, modulating cell survival and promoting differentiation (25). MNDA is expressed in maturating normal and neoplastic myelomonocytic cells, a subset of lymphocytes and some lymphomas but not in other human cells or tissues.…”

Growth advantage of CD34+ cells in trisomy 8 highrisk myelodysplastic syndrome despite enhanced apoptotic signals

“…MDS is a pre-neoplastic condition that frequently develops into overt acute leukaemia [21]. Leukaemic transformation has been presumed to be the result of multiple tandem chromosomal lesions and genetic mutations, some affecting cellular proliferation and others conferring resistance to apoptosis [10].…”