Myeloid Nuclear Differentiation Antigen Research Articles

Quantitative Assessment of Myeloid Nuclear Differentiation Antigen Distinguishes Myelodysplastic Syndrome From Normal Bone Marrow.

Abstract 1754▪▪This icon denotes an abstract that is clinically relevant.Poster Board I-780 IntroductionDefinitive diagnosis and classification of MDS are often difficult because of variable presence of diagnostic criteria and imprecision and ambiguities of interpretation of both morphologic and ancillary data. An objective criterion that reliably distinguishes MDS from normal marrow would greatly facilitate diagnosis, and might contribute to subclassification of MDS. Gene expression profiling has identified marked (7 fold) down-regulation of myeloid nuclear differentiation antigen (MNDA) message in cases of MDS (Hofmann WK, et al, Blood 2002;100:3553-60), and we have previously shown down-regulation of MNDA protein expression in random MDS cases using immunohistochemistry and flow cytometry (Briggs RC, et al. Cancer Research 2006;66:4645-51). To continue our previous analyses, we evaluated MNDA expression in myeloid progenitors using quantitative flow cytometric analysis in MDS and normal control marrow samples. Patients and MethodsThe study included 20 MDS patients receiving only supportive care undergoing bone marrow sampling for clinical purposes, and 19 frequency age-matched normal controls undergoing orthopedic surgery with no antecedent primary hematologic abnormalities. MDS diagnosis was based on 2008 WHO criteria. Quantitative flow cytometric analysis was performed with an FC500 flow cytometer (Beckman Coulter, Fullerton, CA). Cells were treated with CD45-PE and CD34-ECD (Beckman Coulter), washed in PBS with 2% FCS, and permeabilized with PermiFlow. MNDA-Alexa-488 was added at a granulocyte-monocyte specific concentration, with analysis using Winlist 5.0 software (Verity Software, Topsham, ME) with DDE links to ModFitLT 3.0 using modifications of published methods. Differentiating myeloid progenitors were identified as high side scatter/intermediate CD45/CD34-negative cells, with lymphocytes (low side scatter/high CD45/CD34-negative cells) serving as an internal dim MNDA control in each sample. ResultsMDS cases consisted of 12 patients with refractory cytopenia with multilineage dysplasia (RCMD), 3 with refractory anemia with excess blasts-1(RAEB-1), 4 with RAEB-2, and 1 with therapy-related MDS. In myeloid progenitors in MDS patients, the median percent of MNDA-dim cells was 67.4% (range 0.7-97.5%, interquartile range 44.9-82.7%). The analogous median percent of MNDA-dim cells in control patients was 1.2% (range 0.2-13.7%, interquartile range 0.6-2.7%). The area under the ROC curve was 0.96 (p = 9×10-7), indicating almost complete discrimination between cases and controls. 19 of 20 MDS patients demonstrated bimodal distribution of MNDA expression comprising a distinct MNDA-dim population and a separate MNDA-normal population, suggesting an admixture of MDS and normal cells. 18 of 19 control patients demonstrated a single population of MNDA-normal cells without evidence of a bimodal distribution. The single MDS patient with normal MNDA expression had prior clinical and laboratory features suggestive of refractory anemia with ringed sideroblasts. The single pediatric MDS patient had reduced MNDA expression similar to other high grade MDS samples. Patients showed trends for MDS subtype (p = 0.21) and IPSS score (p = 0.07) versus percent MNDA-dim myeloid progenitors. These data demonstrate remarkable sensitivity and specificity for use of MNDA expression to detect MDS. ConclusionsQuantitative flow cytometric analysis of MNDA expression in marrow myeloid progenitors is a promising objective test for diagnosis of MDS, demonstrating a striking difference of MNDA expression in myeloid progenitors in MDS versus control patients. Our results require elaboration with analysis of low grade cases. A single possible low grade MDS case in this series demonstrated MNDA expression identical to normal control samples. Our results also require elaboration in cases constituting the differential diagnosis of MDS to evaluate the clinical utility of MNDA evaluation. The biological significance of down-regulation of MNDA in MDS is uncertain, although MNDA has been implicated in regulation of programmed cell death. Our results suggest a mix of normal and abnormal myelopoiesis in MDS patients, as predicted by cytogenetics in many cases of MDS. In summary, testing of MNDA expression in myeloid progenitors shows great promise as an objective test for diagnosis of MDS in marrow samples. DisclosuresNo relevant conflicts of interest to declare.

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

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 granulocyte-macrophage progenitor cell sensitivity to TRAIL-induced programmed cell death.

Dysregulated Expression of Myeloid Nuclear Differentiation Antigen (MNDA) in MDS: Possible Role in TRAIL-Induced Apoptosis.

A reduced level of MNDA expression has been reported with gene expression profiling in both sporadic and familial MDS. We undertook studies to evaluate MNDA protein expression in MDS, and its possible functional significance. Patients (n=7) clinical histories, lab data, cytogenetics, and morphology were reviewed blinded to study results to confirm diagnoses. Patients had Refractory Cytopenia with Multilineage Dysplasia (n=6) or Refractory Anemia with Excess Blasts-1 (n=1)(WHO). Patients lacking primary marrow disease (n=5) were used as controls. Samples were assessed with multiparametric flow cytometry (MPFC) for CD45 antigen density, log side scatter, CD34, CD71, and MNDA (using a specific rat monoclonal antibody) with an FC500 (Beckman-Coulter) flow cytometer, and analyzed with Winlist 5.0 and ModFitLT 3.0 (Verity Software) using published methods and ECFI-generated algorithms. Analyses were blinded to clinical results. Immunohistochemistry (IHC) for MNDA was performed using the same antibody and published methods. Both MPFC and IHC demonstrated MNDA expression in MDS predominantly in granulocyte-macrophage (G-M) progenitors, similar to controls. G-M progenitors in MDS demonstrated reduced MNDA protein expression compared to controls, with 3 patterns: uniform reduced MNDA protein, a mix of normal and absent MNDA protein, or a mix of reduced and absent MNDA protein. We interpret the normal expression in some cases as consistent with presence of a mixture of normal and MDS cells, while the mix of reduced and absent expression may represent clonal evolution of MDS. To evaluate possible functional significance of MNDA expression we used stable K562 clones that express ectopic MNDA protein via retroviral transduction. Parental K562 cells lack MNDA expression. Compared to parental K562, ectopic expression of MNDA failed to protect cells from intrinsic path apoptosis induced by genotoxic agents (mechlorethamine, etoposide, cisplatin) or H2O2. Apoptosis was evaluated by morphology, TUNEL assay, trypan blue exclusion, and phosphorylation of Histone H2B at serine 14 (a specific marker of apoptosis). In sharp contrast, ectopic MNDA expression provided marked protection of cells from extrinsic path apoptosis induced by TRAIL (TNF-related apoptosis inducing ligand) exposure. Disordered apoptosis is hypothesized to be a factor in MDS pathogenesis. Our results indicate MNDA promotes viability in myeloid progenitors, and its down-regulation in MDS might relate to the G-M progenitor sensitivity to TRAIL-induced apoptosis that has been reported in MDS.

Variable expression of human myeloid specific nuclear antigen MNDA in monocyte lineage cells in atherosclerosis

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. MNDA and related proteins appear to modulate the activity of transcription factors and in some cases have a role in mediating cell death. The expression of MNDA was characterized in normal and diseased human aorta. MNDA positive cells double labeled for CD68 in all tissue examined. Twenty percent of normal aortas were negative or contained rare MNDA positive cells while other normal aorta contained more frequent positive cells. In atherosclerotic aorta, the number of MNDA positive cells increased with progression of disease. In normal and early lesions, MNDA positive cells adjacent to the endothelium generally displayed a strong MNDA reactivity associated with small amount of CD68 reactive cytoplasm. In the same sections, MNDA positive cells at increasing distances from the endothelium displayed lower MNDA reactivity and were associated with larger amounts of CD68 reactive cytoplasm. Foam cells in fatty streaks exhibited MNDA reactivity that ranged from strong to weak or negative. In advanced lesions, cells in the shoulder and those in fibrous tissue surrounding an atheroma were highly reactive for MNDA. However, only a fraction of the CD68 positive foam cells near the lipid core under the cap and shoulder contained MNDA reactivity. The variation in MNDA expression appeared to change with phenotypic specialization of monocytes in atherosclerosis consistent with its association with inflammation and suspected roles in regulating gene expression or in mediating cell death.

Myeloid Nuclear Differentiation Antigen (MNDA) Protein Expression in Myelodysplastic Syndrome (MDS) Is Reduced in Maturing Myeloid Cells.

Expression of the human MNDA protein is restricted to hematopoietic cells, and occurs at uniformly high level only in the normal granulocyte/monocyte lineage. Myeloblasts and all later stages of the lineage express MNDA, while stem cells do not (Hum Pathol 1999; 30:1040). Gene expression analyses of MDS cases have shown that MNDA mRNA is significantly down regulated in familial MDS and in high-risk sporadic MDS cases (Blood 2000; 100:3553 and Leukemia 2004; 18:449). We evaluated MNDA protein expression in patients with MDS.Methods: We directly conjugated Alexa 488 (Molecular Probes) to a rat monoclonal antibody specific for MNDA for use in multiparameter cytometric analysis with CD45/CD34 and DRAQ5 (DNA content). Patients' (n=17) clinical histories, laboratory data, cytogenetics, and morphology were reviewed for confirmation of diagnoses and blinded to study results. Patients lacking primary marrow disease (n=9) were used as controls. Analysis was performed using Winlist 5.0 software (Verity Software) with DDE links to ModFitLT 3.0 using modifications of published methods along with Esoterix Center for Innovation generated algorithms. Analyses were blinded to clinical results.Results: The normal dataset revealed MNDA expression in expected cell populations, with only a small subset of CD34+ cells exhibiting MNDA (7.5% on average). Expression of MNDA protein in maturing myeloid forms in normals was consistently greater than in MDS samples (MFI=802 vs. 569 in MDS; MFI=mean fluorescence intensity defined by the linear mean of each population). Six of 17 MDS cases displayed greater than 10% maturing myeloid forms lacking MNDA protein expression (never observed in normals). The % MNDA+/CD34+ cells was identical in the two datasets (7.5% in normal vs. 7.6% in MDS).Discussion: Our results suggest that MNDA protein expression in MDS patients follows a pattern similar to that in gene expression analyses. We additionally demonstrate that MNDA protein expression at the cellular level is variable in MDS, versus uniform expression in normals; parallel data for MNDA message expression at the cellular level is not available. The finding of MNDA-negative myeloid forms in MDS may have diagnostic utility, and may provide insight into both impaired myeloid differentiation in MDS and the biologic role of MNDA.

Differentially expressed genes in adult familial myelodysplastic syndromes.

The precise genetic events leading to myelodysplastic syndromes (MDSs) and leukemic transformation remain poorly defined. Even less is known about adult familial MDS. We report an adult MDS family in whom enriched tissue-specific transcripts were derived by subtractive hybridization of cDNA from the mononuclear and CD34+ cells of affected and unaffected family members. These expression libraries were then hybridized to Genome Discovery arrays containing 18 404 genes and expressed sequence tags, and several clusters of differentially expressed genes were identified. 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). Another group of 36 genes was overexpressed (>5-fold), and these encoded proteins belonging to signaling pathways, such as Ras- and Fos-related genes. The top two genes downregulated in this MDS family, ZNF140 and MNDA, were similarly altered in another MDS family, and in some cases of sporadic MDS. Our data suggest that we have identified genes differentially expressed in adult familial MDS, and that alteration of some of these genes may also be important for the evolution of different stages or severity of sporadic MDS.

A 588-gene microarray analysis of the peripheral blood mononuclear cells of spondyloarthropathy patients.

To identify genes which are more highly expressed in the peripheral blood mononuclear cells (PBMC) of patients with spondyloarthropathy (SpA), rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in comparison to normal subjects. A 588-gene microarray was used as a screening tool to select a panel of such genes from PBMC of these subjects and of normal subjects. Results were then validated by reverse transcription-polymerase chain reaction (RT-PCR). The following genes were more highly expressed in arthritis patients than in normal subjects: macrophage differentiation marker MNDA (myeloid nuclear differentiation antigen), MRP8 and MRP14 (migratory inhibitory factor-related proteins); signalling molecules JAK3 (janus kinase 3) and MAP kinase p38 (mitogen-activated protein kinase); receptors TNFR2/p75, C-C-chemokine receptor type 1 (CCR1), C-X-C-chemokine receptor type 4 (CXCR4) and integrin beta1; and the cytokines/chemokines interleukin (IL) 1beta and IL-8. Expression of CXCR4 was unexpectedly high among all arthritis subjects. Using RT-PCR, ELISA and immunohistology, expression of stromal cell-derived factor 1 (SDF-1) was demonstrated in arthritis joints. The CXCR4/SDF-1 is a potential pro-inflammatory axis for RA, PsA and SpA.

Retroviral mediated expression of the human myeloid nuclear antigen in a null cell line upregulates Dlk1 expression.

The human myeloid nuclear differentiation antigen (MNDA) is a hematopoietic cell specific nuclear protein. MNDA and other related gene products interact with and alter the activity of a large number of proteins involved in regulating specific gene transcription. MNDA and related genes exhibit expression characteristics, which suggest functions unique to specific lineages of cells, in addition to mediating the effects of interferons. Cells of the human K562 myeloid line do not express MNDA and are relatively immature compared to lines that express MNDA (HL-60, U937, and THP1). The hypothesis that MNDA influences the expression of specific genes was tested by creating MNDA expressing K562 cells using stable retroviral mediated gene transfer followed by evaluation of transcription profiles. 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. 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. The effects on Dlk1 were also confirmed by Northern blotting. Dlk1 is essential for normal hematopoiesis and abnormal expression is a proposed marker of myelodysplastic syndrome. Additional screening of transcription profiles after induced erythroid and megakaryoblastic differentiation showed no additional gene transcripts altered by the presence of MNDA. These results indicate that MNDA alters expression of a gene essential for normal hematopoiesis.

Identification of novel markers for monitoring minimal residual disease in acute lymphoblastic leukemia

AbstractTo identify new markers of minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL), gene expression of leukemic cells obtained from 4 patients with newly diagnosed ALL was compared with that of normal CD19+CD10+ B-cell progenitors obtained from 2 healthy donors. By cDNA array analysis, 334 of 4132 genes studied were expressed 1.5- to 5.8-fold higher in leukemic cells relative to both normal samples; 238 of these genes were also overexpressed in the leukemic cell line RS4;11. Nine genes were selected among the 274 overexpressed in at least 2 leukemic samples, and expression of the encoded proteins was measured by flow cytometry. Two proteins (caldesmon and myeloid nuclear differentiation antigen) were only weakly expressed in leukemic cells despite strong hybridization signals in the array. By contrast, 7 proteins (CD58, creatine kinase B, ninjurin1, Ref1, calpastatin, HDJ-2, and annexin VI) were expressed in B-lineage ALL cells at higher levels than in normal CD19+CD10+ B-cell progenitors (P < .05 in all comparisons). CD58 was chosen for further analysis because of its abundant and prevalent overexpression. An anti-CD58 antibody identified residual leukemic cells (0.01% to 1.13%; median, 0.03%) in 9 of 104 bone marrow samples from children with ALL in clinical remission. MRD estimates by CD58 staining correlated well with those of polymerase chain reaction amplification of immunoglobulin genes. These results indicate that studies of gene expression with cDNA arrays can aid the discovery of leukemia markers.

Transcription and growth regulatory functions of the HIN-200 family of proteins.

Interferons have been shown to exert antiviral, cell growth regulatory, and immunomodulatory effects on target cells (16, 37). Both type I (α and β) and type II (γ) interferons regulate cellular activities by specifically inducing the expression or activation of endogenous proteins that perform distinct biological functions. The HIN-200 (hematopoietic interferon-inducible nuclear proteins with a 200-amino-acid repeat) gene family found on human and mouse chromosome 1 is positively regulated by type I and II interferons (15, 27, 30). The HIN-200 family of proteins consists of a number of highly homologous human and murine proteins with similar primary amino acid sequences and biological characteristics. The human HIN-200 family members include IFI 16 (39), the myeloid nuclear differentiation antigen (MNDA) (2, 18), and AIM-2 (absent in melanoma) (17), while the mouse HIN-200 family members include p202 (3), p203 (20), p204 (3), and D3 (38). There are a number of reviews that elegantly outline the biochemical characteristics of these proteins and their patterns of expression (15, 27, 30). Recently, there have been a number of reports examining possible cellular functions of HIN-200 proteins. It is now clear that these proteins play a role in modulating cell growth and perhaps in vivo differentiation, and the newest member of the HIN-200 family, AIM-2, has been identified as a possible tumor suppressor protein. Some family members are transcriptional regulators, acting either directly by binding DNA at a promoter or indirectly by modulating the function of other cellular transcription factors. Clearly, there is much still to learn about the biological functions of these proteins and how significant a role they play during an interferon response. While it is clear that the human and mouse family members share many biochemical and structural characteristics, it is unclear which, if any, of the currently identified murine HIN-200 proteins are functional homologs of the different human HIN-200 family members. This review will briefly cover the structural and biochemical properties of HIN-200 proteins but will concentrate on the molecular and biological functions of these molecules.

Human hematopoietic cell specific nuclear protein MNDA interacts with the multifunctional transcription factor YY1 and stimulates YY1 DNA binding

The human myeloid nuclear differentiation antigen, MNDA, is expressed only in myelomonocytic and a subset of B lymphoid hematopoietic cells. MNDA is uniformly distributed throughout the interphase cell nucleus and associates with chromatin, but does not bind specific DNA sequences. We recently demonstrated that MNDA binds nucleolin and nucleophosmin/NPM/B23 and both of these nuclear proteins bind the ubiquitous zinc finger transcription factor YY1. Investigations of the possible effect of MNDA on the interaction between YY1 and NPM, showed that MNDA bound YY1 directly under both in vitro and in vivo conditions. The MNDA-YY1 interaction enhanced the affinity of YY1 for its target DNA and decreased its rate of dissociation. The N-terminal half (200 amino acids) of MNDA was sufficient for maximum enhancement of YY1 DNA binding and a portion of this sequence was responsible for binding YY1. MNDA participated in a ternary complex with YY1 and the YY1 target DNA element. The results show that MNDA affects the ability of YY1 to bind its target DNA sequnce and that MNDA participates in a ternary complex possibly acting as a cofactor to impart lineage specific features to YY1 function. J. Cell. Biochem. 70:489–506, 1998. © 1998 Wiley-Liss, Inc.

Human hematopoietic cell specific nuclear protein MNDA interacts with the multifunctional transcription factor YY1 and stimulates YY1 DNA binding

The human myeloid nuclear differentiation antigen, MNDA, is expressed only in myelomonocytic and a subset of B lymphoid hematopoietic cells. MNDA is uniformly distributed throughout the interphase cell nucleus and associates with chromatin, but does not bind specific DNA sequences. We recently demonstrated that MNDA binds nucleolin and nucleophosmin/NPM/B23 and both of these nuclear proteins bind the ubiquitous zinc finger transcription factor YY1. Investigations of the possible effect of MNDA on the interaction between YY1 and NPM, showed that MNDA bound YY1 directly under both in vitro and in vivo conditions. The MNDA-YY1 interaction enhanced the affinity of YY1 for its target DNA and decreased its rate of dissociation. The N-terminal half (200 amino acids) of MNDA was sufficient for maximum enhancement of YY1 DNA binding and a portion of this sequence was responsible for binding YY1. MNDA participated in a ternary complex with YY1 and the YY1 target DNA element. The results show that MNDA affects the ability of YY1 to bind its target DNA sequnce and that MNDA participates in a ternary complex possibly acting as a cofactor to impart lineage specific features to YY1 function.

The Human Interferon-inducible Protein, IFI 16, Is a Repressor of Transcription

IFI 16 is a member of a family of interferon-inducible proteins, including the human MNDA (myeloid nuclear differentiation antigen), the recently identified AIM-2 (absent in melanoma), and the homologous murine molecules, p202, p204, and D3. IFI 16 contains a domain at the amino terminus capable of binding double-stranded DNA and a bipartite nuclear localization signal. No molecular or biological function has been assigned to any of the human family members, although a role in transcription regulation has been proposed. In the present study, we show IFI 16 fused to the GAL4 DNA binding domain can function as a transcriptional repressor. IFI 16-mediated repression is not dependent on the position or distance of IFI 16 binding, relative to the site of transcription initiation, and it can significantly repress when only one GAL4 DNA element is present in the promoter. We mapped the transcriptional repression domains to the 200 amino acid repeat regions common to all human and mouse family members. We also demonstrate that wild type IFI 16 can repress transcription of a reporter gene containing the minimal promoter region of the human cytomegalovirus UL54 gene. Thus, IFI 16 is a transcriptional repressor, with a modular structure typical of many known transcription regulators.

Structure and function analysis of the human myeloid cell nuclear differentiation antigen promoter: evidence for the role of Sp1 and not of c-Myb or PU.1 in myelomonocytic lineage-specific expression.

The human myeloid nuclear differentiation antigen (MNDA) is expressed specifically in maturing cells of the myelomonocytic lineage and in monocytes and granulocytes. Epitope enhancement was used to confirm the strict lineage- and stage-specific expression of MNDA in bone marrow as well as in other paraffin-embedded fixed tissues. A 1-kb region of the gene that includes 5' flanking sequence was reported earlier to contain functional promoter activity and was specifically demethylated in expressing cells in contrast to null cells. Further analysis has revealed that this 1-kb fragment promotes higher reporter gene activity in MNDA-expressing cells than non-expressing cells, indicating cell-specific differences in transactivation. This sequence contains consensus elements consistent with myeloid-specific gene expression, including a PU.1 consensus site near the major transcription start site and a cluster of c-Myb sites located several hundred bases upstream of this region. However, analysis of deletion mutants localized nearly all of the promoter activity to a short region (-73 to -16) that did not include the cluster of c-Myb sites. A 4-bp mutation of the core Sp1 consensus element (GC box) (-20) reduced overall promoter activity of the 1-kb fragment. Mutation of the PU.1 site did not significantly affect promoter activity. Only a small region (-35 to +22) including the Sp1 element and transcription start site, but not the PU.1 site was footprinted. The 4-bp mutation of the core Sp1 consensus element abolished footprinting at the site and an antibody super-shift reaction showed that Sp1 is one of the factors binding the consensus site. The Sp1 site also co-localizes with a DNase I hypersensitive site. The results indicate that DNA methylation, chromatin structure, and transactivation at an Sp1 site contribute to the highly restricted expression of this myelomonocytic lineage specific gene.

The closely linked genes encoding the myeloid nuclear differentiation antigen (MNDA) and IFI16 exhibit contrasting haemopoietic expression.

Recently, a novel family of highly homologous interferon (IFN)-inducible nuclear proteins have been described in both humans and in the mouse, whose expression is associated with myeloid differentiation. IFI16 and the myeloid nuclear differentiation antigen (MNDA) are the two known human members of this family, characterized by their interferon inducibility, and structurally by the presence of at least one copy of a conserved 200 amino acid motif. IFI16 has been shown to be constitutively expressed in lymphoid cell lines, but is inducible with IFN-{alpha} and -{gamma}, and chemical agents eliciting differentiation in myeloid cell lines such as HL-60. By contrast, MNDA is specifically expressed in myeloid cells from the promyelocytic stage onwards, and is inducible only with IFN-{alpha}. Both proteins are localized to the nucleus, and have been shown to bind to DNA, properties which allude to a putative function as transcription factors. 20 refs., 3 figs.