Disease relevance of MNDA

• The human myeloid leukemia cell lines, HL-60, U937, and THP-1, express similar levels of immunochemically detectable MNDA [1].
• In advanced lesions, cells in the shoulder and those in fibrous tissue surrounding an atheroma were highly reactive for MNDA [2].
• Meaningful similarities were observed in extended regions between the MNDA and the reported beta interferon-inducible proteins, 202 and 204, from Ehrlich ascites mouse tumor cells [3].
• Reduced levels of human myeloid nuclear differentiation antigen (MNDA) gene transcripts have been detected in both familial and sporadic cases of myelodysplastic syndromes (MDS) [4].
• An extensive immunocytochemical evaluation of fixed tissues confirmed MNDA expression in normal maturing granulocytes and monocytes and in acute nonlymphocytic leukemias and chronic myelogenous leukemia [5].

High impact information on MNDA

• In addition, one mouse gene in the Ifi-200 gene family and the human MNDA and IFI 16 genes show expression and/or regulation restricted to cells of the hematopoietic system, suggesting that these genes participate in blood cell-specific responses to interferons [6].
• Characterization of the MNDA gene showed that it is a single-copy gene and localized to human chromosome 1q 21-22 within the large linkage group conserved between mouse and human that contains the Ifi-200 gene family [6].
• We have previously shown that the human myeloid cell nuclear differentiation antigen (MNDA) is expressed at both the antigen and mRNA levels specifically in human monocytes and granulocytes and earlier stage cells in the myeloid lineage [6].
• The human myeloid cell nuclear differentiation antigen gene is one of at least two related interferon-inducible genes located on chromosome 1q that are expressed specifically in hematopoietic cells [6].
• We tested the hypothesis that MNDA is involved in the regulation of programmed cell death in human myeloid hematopoietic cells [4].

Biological context of MNDA

• MNDA and related proteins appear to modulate the activity of transcription factors and in some cases have a role in mediating cell death [2].
• The MNDA has been isolated by using a monoclonal antibody affinity matrix and reversed-phase high performance liquid chromatography [3].
• In addition, a 12-base sequence matching the interferon-stimulated response element consensus sequence [GAAAN(N)GAAA] is located in the 5' untranslated region of the MNDA cDNA [7].
• MNDA is uniformly distributed throughout the interphase cell nucleus and associates with chromatin, but does not bind specific DNA sequences [8].
• Two macroarrays containing a total of 2,350 cDNAs of known genes showed a specific up-regulation of Dlk1 expression in MNDA expressing K562 cell clones [9].

Anatomical context of MNDA

• Therefore, IFI 16 and MNDA are members of a novel family of human DNA-binding proteins whose expression is associated with myeloid cell differentiation induced by cytokines and chemical agents [10].
• Variable expression of human myeloid specific nuclear antigen MNDA in monocyte lineage cells in atherosclerosis [2].
• The effect of interferon alpha on the MNDA mRNA is also observed in the cell lines HL-60, U937, and THP-1 [1].
• The expression and the primary structure of the MNDA indicates that it plays a role in the granulocyte/monocyte cell-specific response to interferon [7].
• MNDA (human myeloid nuclear differentiation antigen) is expressed in specific lineages of hematopoietic cells and most notably at high levels in macrophages at sites of inflammation [2].

Associations of MNDA with chemical compounds

• Intact cells were treated with the reversible cross-linking agent cis-diamminedichloroplatinum(II) and the MNDA levels in the isolated protein-DNA complexes were determined [11].
• A cesium chloride gradient analysis of the nucleic acid-protein fraction isolation from cis-diamminedichloroplatinum(II)-treated, monocyte-induced HL-60 cells documented the authenticity of the association between the MNDA and DNA [11].
• 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) [4].
• Although both antibody affinity matrices exhibited the same antigen binding capacities, the matrix prepared using carbonyldiimidazole-activated agarose bound the MNDA with a high level of specificity while the matrix prepared from CNBr-activated agarose bound numerous other nuclear proteins [12].
• cis-diamminedichloroplatinum(II) cross-linking of the human myeloid cell nuclear differentiation antigen to DNA in HL-60 cells following 1,25-dihydroxy vitamin D3-induced monocyte differentiation [11].

Physical interactions of MNDA

• Nuclear IFI 16 was able to bind double-stranded DNA in vitro and exhibited a similar elution profile from DNA-cellulose as previously observed for MNDA and 204 [10].
• MNDA participated in a ternary complex with YY1 and the YY1 target DNA element [8].
• However, MNDA did bind the NPM-MLF1 product of the t(3;5) that contains the N-terminal 175 residues of NPM [13].
• Microsequence analysis showed that MNDA bound the 100 kDa nucleolin protein [14].

Regulatory relationships of MNDA

• By contrast, three lymphoblastoid cell lines (immortalized in vitro with Epstein-Barr virus) were weakly positive and MNDA was up-regulated by interferon-alpha (IFN-alpha) treatment [15].

Other interactions of MNDA

• The closely linked genes encoding the myeloid nuclear differentiation antigen (MNDA) and IFI16 exhibit contrasting haemopoietic expression [16].
• One family is encoded by several structurally related genes located on murine chromosome 1 (Ifi 200 cluster) and three homologous genes (MNDA, IFI 16 and AIM2) located on human chromosome 1 as well, within a linkage group highly conserved between mouse and human [17].
• A group of 21 genes was underexpressed (>5-fold) in affected vs unaffected family members, and among these were transcription factors and genes involved in myeloid differentiation, such as ZNF140 and myeloid nuclear differentiation antigen (MNDA) [18].
• The MNDA-YY1 interaction enhanced the affinity of YY1 for its target DNA and decreased its rate of dissociation [8].
• MNDA positive cells double labeled for CD68 in all tissue examined [2].

Analytical, diagnostic and therapeutic context of MNDA

• Real time quantitative RT-PCR analysis confirmed an average of over 3- and 7-fold upregulation of Dlk1 in two clones of MNDA expressing K562 cells [9].
• Immunoprecipitation assay revealed that LANA interacted with MNDA in a mammalian embryonic kidney cell line [19].

References