Objective: We aimed to explore the clinical value of MDS1 and EVI1 complex locus (MECOM) in lung adenocarcinoma (LUAD). Methods: Bioinformatics and experimental validation confirmed MECOM expression levels in LUAD. The value of MECOM was analyzed by receiver operating characteristic (ROC) curve and Cox regression analysis. Results: Serum MECOM levels were lower in LUAD and correlated with gender, TNM stage, tumor size, lymph node metastasis and distant metastasis. The ROC curve showed that the area under the curve of MECOM was 0.804 for LUAD and, of note, could reach 0.889 for advanced LUAD; specificity was up to 90%. Conclusion: MECOM may contribute to independently identifying LUAD patients, particularly in advanced stages.
Lung adenocarcinoma is a common type of lung cancer with a high incidence and death rate. However, clinical indicators that effectively identify lung adenocarcinoma patients are still lacking. The protein encoded by the MECOM gene is a DNA-binding protein regulating gene expression, which has been found to play a cancer-promoting role in many cancers, but we found that it may play a cancer-suppressing role in lung adenocarcinoma. This study aimed to confirm whether MECOM can be a predictor for lung adenocarcinoma. Our results showed that lung adenocarcinoma patients had lower serum MECOM levels than healthy people, and patients with lower MECOM levels had a shorter survival rate. That is, patients with lower serum MECOM levels may indicate a high risk of developing lung adenocarcinoma and death. Thus, the MECOM gene is expected to be a predictor associated with the risk of developing lung adenocarcinoma and death.

In acute myeloid leukemia (AML), EVI1 rearrangement represented by inv(3)(q21q26) or t(3;3)(q21;q26) causes EVI1 overexpression via structural rearrangement of an enhancer, and confers poor prognosis. My colleagues and I performed a mutational analysis of EVI1-rearranged myeloid neoplasms and identified SF3B1, a core RNA splicing factor, as the most commonly co-mutated gene. Indeed, latent leukemia development in transgenic mice bearing the humanized inv(3)(q21q26) allele was significantly accelerated by co-occurrence of Sf3b1 mutation. Intriguingly, we found that this SF3B1 mutant induced mis-splicing of EVI1 itself, which generated an aberrant EVI1 isoform with in-frame insertion of 6 amino acids near the DNA-binding domain of EVI1. This aberrant EVI1 isoform exhibited DNA-binding activity different from wild-type EVI1 and significantly enhanced the self-renewal capacity of murine hematopoietic stem cells. We also identified the cryptic branch point and exonic splicing enhancer required for this EVI1 mis-splicing induced by the SF3B1 mutant. These data provide a basis for further elucidation of the molecular mechanism and potential therapeutic candidates for EVI1-rearranged AML.

In the present study, it was aimed to investigate the effects and potential mechanisms of heat shock protein B7 (HSPB7) on lung adenocarcinoma (LUAD). Bioinformatic analysis was performed to explore the association between HSPB7 expression and patients with LUAD. MTT, colony formation, wound healing and Transwell assays were performed to examine the proliferative, migratory and invasive abilities of H1975 and A549 cells. Western blot analysis was conducted to determine the corresponding protein expression. Co‑Immunoprecipitation and Chromatin immunoprecipitation assays were carried out to reveal the interaction between HSPB7 and myelodysplastic syndrome 1 and ecotropic viral integration site 1 complex locus (MECOM). In addition, an animal model was conducted by the subcutaneous injection of A549 cells into BALB/c nude mice, and tumor weight and size were measured. HSPB7 was downregulated in LUAD tissues and cells, and its expression level correlated with patient prognosis. Cell functional data revealed that silencing of HSPB7 promoted lung cancer cell proliferation, migration, invasion and epithelial mesenchymal transition (EMT); whereas overexpression of HSPB7 led to the opposite results. Furthermore, bioinformatics analysis showed that HSPB7 inhibited glycolysis. HSPB7 decreased glucose consumption, lactic acid production, and lactate dehydrogenase A, hexokinase 2 and pyruvate kinase muscle isoform 2 protein levels. The results demonstrated that MECOM was a transcription factor of HSPB7. Collectively, these results suggested that HSPB7 is regulated by MECOM, and that HSPB7 attenuates LUAD cell proliferation, migration, invasion and EMT by inhibiting glycolysis.

Stem cell gene therapy using the MFGS-gp91phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient\'s refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6 months. Thirty-two months after gene therapy, the patient developed myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12 months after gene therapy. However, the patient exhibited normal hematopoiesis until the onset of MDS, suggesting that MECOM transactivation contributed to clonal hematopoiesis, and the blast transformation likely arose after the acquisition of additional genetic lesions. In whole-genome sequencing, the biallelic loss of the WT1 tumor suppressor gene, which occurred immediately before tumorigenesis, was identified as a potential candidate genetic alteration. The provirus CYBB cDNA in the blasts contained 108 G-to-A mutations exclusively in the coding strand, suggesting the occurrence of APOBEC3-mediated hypermutations during the transduction of CD34-positive cells. A hypermutation-mediated loss of oxidase activity may have facilitated the survival and proliferation of the clone with MECOM transactivation. Our data provide valuable insights into the complex mechanisms underlying the development of leukemia in X-CGD gene therapy.

MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance. The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections. The syndrome, usually diagnosed in the neonatal period because of severe thrombocytopenia, is caused by mutations in the MECOM gene, encoding for the transcription factor EVI1. The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood. In a paediatric patient affected by severe thrombocytopenia, we identified a novel variant of the MECOM gene (p.P634L), whose effect was tested on pAP-1 enhancer element and promoters of targeted genes showing that the mutation impairs the repressive activity of the transcription factor. Moreover, we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT.

MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development.

Inherited bone marrow failure (BMF) syndromes are genetically diverse - more than 100 genes have been associated with those syndromes and the list is rapidly expanding. Risk assessment and genetic counseling of patients with recently discovered BMF syndromes is inherently difficult as disease mechanisms, penetrance, genotype-phenotype associations, phenotypic heterogeneity, risk of hematologic malignancies and clonal markers of disease progression are unknown or unclear. This review aims to shed light on recently described BMF syndromes with sparse concise data and with an emphasis on those associated with germline variants in ADH5/ALDH2, DNAJC21, ERCC6L2 and MECOM. This will provide important data that may help to individualize and improve care for these patients.

The transcription factors MECOM, PAX8, SOX17 and WT1 are candidate master regulators of high-grade serous \'ovarian\' cancer (HGSC), yet their cooperative role in the hypothesized tissue of origin, the fallopian tube secretory epithelium (FTSEC) is unknown. We generated 26 epigenome (CUT&TAG, CUT&RUN, ATAC-seq and HiC) data sets and 24 profiles of RNA-seq transcription factor knock-down followed by RNA sequencing in FTSEC and HGSC models to define binding sites and gene sets regulated by these factors in cis and trans. This revealed that MECOM, PAX8, SOX17 and WT1 are lineage-enriched, super-enhancer associated master regulators whose cooperative DNA-binding patterns and target genes are re-wired during tumor development. All four TFs were indispensable for HGSC clonogenicity and survival but only depletion of PAX8 and WT1 impaired FTSEC cell survival. These four TFs were pharmacologically inhibited by transcriptional inhibitors only in HGSCs but not in FTSECs. Collectively, our data highlights that tumor-specific epigenetic remodeling is tightly related to MECOM, PAX8, SOX17 and WT1 activity and these transcription factors are targetable in a tumor-specific manner through transcriptional inhibitors.

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self-renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM-associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM-associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype-to-phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non-hematologic clinical features allows for rapid molecular diagnosis, early identification of life-threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.

A 62-year-old woman was presented at our hospital with visual disturbance. An ocular examination revealed bilateral Roth spots. Laboratory data revealed leukocytosis (236,200 µl) with an excess blast (11%). Physical examination and computed tomography (CT) showed systemic lymphadenopathy. A bone marrow examination revealed a composition of 9.2% blast. Chromosomal analysis on bone marrow cells revealed 46,XX,t (3;12)(q26.2;p13),t (9;22)(q34.1;q11.2) in 80% of metaphases (16/20). Inguinal lymph node biopsy revealed diffuse proliferation of myeloperoxidase (MPO)-positive abnormal cells. Fluorescence in situ hybridization analysis was used to detect the BCR-ABL1 fusion gene and split the signals of MECOM and ETV6. She was diagnosed with de-novo chronic myeloid leukemia (CML) extramedullary blast crisis. She received tyrosine kinase inhibitor (TKI) combination chemotherapy and allogeneic hematopoietic stem cell transplantation and achieved a major molecular response. In this study, we reported a case of CML in blast-phase initially presenting as extramedullary, in which cytogenetic and molecular analyses were useful in the staging method.