Heterozygous mutations in GATA2 underlie different syndromes, previously described as monocytopenia and mycobacterial avium complex infection (MonoMAC); dendritic cell, monocytes, B- and NK lymphocytes deficiency (DCML); lymphedema, deafness and myelodysplasia (Emberger syndrome) and familiar myelodysplastic syndrome/acute myeloid leukemia (MDS / AML). Onset and severity of clinical symptoms vary and preceding cytopenias are not always present. We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to GATA2 mutation. Exome sequencing revealed a somatic ASXL1 mutation and the patient underwent allogeneic stem cell transplantation successfully.

The modern classification of pituitary neuroendocrine tumors relies mainly on immunohistochemistry for pituitary transcription factors, hormones, and other biomarkers, including low molecular weight cytokeratins. The transcription factor GATA2 is required for development of gonadotrophs and thyrotrophs but has not been used for classification of pituitary tumors. Because of genomic paralogy of GATA2 and GATA3, we postulated that GATA3 immunohistochemistry may detect GATA2 in the adenohypophysis. We examined 151 tumors originating from Ondokuz Mayis University, Turkey (n = 83) and University Health Network, Canada (n = 68). Initially, 83 tumors (26 gonadotroph, 24 somatotroph, 17 corticotroph, 12 lactotroph, 2 poorly differentiated Pit-1 lineage tumors that expressed TSH and 2 null cell tumors) from Ondokuz Mayis University were investigated with the GATA3 monoclonal antibody L50-823. Retrospective review of the files of University Health Network identified 68 tumors (43 gonadotroph, 3 somatotroph, 2 lactotroph, 1 mammosomatotroph, 9 corticotroph, 7 poorly differentiated Pit-1 lineage tumors with TSH expression, 2 plurihormonal tumors with TSH expression and 1 null cell tumor) that were examined with the same GATA3 antibody and served as a validation cohort. All somatotroph, lactotroph and mammosomatotroph tumors and the null cell tumors were negative for GATA3. Sixty-eight (98.5%) gonadotroph tumors were positive for GATA3; 64 had diffuse reactivity. Two plurihormonal tumors with TSH expression and eight (88.8%) poorly differentiated Pit-1 lineage tumors with variable TSH expression were positive for GATA3. One of 26 (3.8%) corticotroph tumors was diffusely positive for GATA3. This study shows that GATA3 immunoreactivity is characteristic of pituitary gonadotroph and TSH-producing tumors. This finding expands the pattern of transcription factors that are used to classify adenohypophysial tumors and is important in the differential diagnosis of sellar tumors, as GATA3 expression is also a feature of primary sellar paragangliomas as well as carcinomas that may metastasize to the sella.

Tegmental nuclei in the ventral midbrain and anterior hindbrain control motivated behavior, mood, memory, and movement. These nuclei contain inhibitory GABAergic and excitatory glutamatergic neurons, whose molecular diversity and development remain largely unraveled. Many tegmental neurons originate in the embryonic ventral rhombomere 1 (r1), where GABAergic fate is regulated by the transcription factor (TF) Tal1. We used single-cell mRNA sequencing of the mouse ventral r1 to characterize the Tal1-dependent and independent neuronal precursors. We describe gene expression dynamics during bifurcation of the GABAergic and glutamatergic lineages and show how active Notch signaling promotes GABAergic fate selection in post-mitotic precursors. We identify GABAergic precursor subtypes that give rise to distinct tegmental nuclei and demonstrate that Sox14 and Zfpm2, two TFs downstream of Tal1, are necessary for the differentiation of specific tegmental GABAergic neurons. Our results provide a framework for understanding the development of cellular diversity in the tegmental nuclei.

Keywords: Gata2; Notch; Sox14; Tal1; Zfpm2; brainstem; neurogenesis; rhombomere 1; single cell transcriptomics; transcription factor.

Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other nonmalignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant-related mortality, particularly in patients with comorbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome, n = 3; Diamond Blackfan anemia, n = 4; GATA2 deficiency, n = 2; paroxysmal nocturnal hemoglobinuria, n = 4; and an undefined marrow failure disorder, n = 1) who underwent HCT on a prospective, phase II, multicenter clinical trial. Patients were given HLA-matched related (n = 2) or unrelated (n = 12) grafts after conditioning with treosulfan (42 g/m2), fludarabine (150 mg/m2), ± thymoglobulin (n = 11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.

GATA2 deficiency is characterized by monocytopenia, deficiency of dendritic cells, and a variable degree of lymphocytopenia affecting B cells and NK cells, leading to an enhanced risk of mycobacterial, viral, and fungal infections. Here we present a patient with a heterozygous intronic GATA2 mutation who acquired a fatal disseminated mycosis due to the black yeast-like fungus Arthrocladium fulminans following an infection with Mycobacterium sherrisii. This case illustrates that in patients with severe uncommon infections, immunodeficiency syndromes must be ruled out.

Mycobacterium kansasii usually causes chronic pulmonary infections in immunocompetent patients. In contrast, disseminated M. kansasii disease is commonly associated with advanced human immunodeficiency virus infection, but is reported infrequently in other immunocompromised patients.

To identify common clinical manifestations and potential risk factors for M. kansasii infection in patients with GATA2 deficiency.

We reviewed M. kansasii disease associated with GATA2 deficiency at one institution and disease associated with primary and other immunodeficiencies reported in the literature.

Nine patients with GATA2 deficiency developed M. kansasii infections. Six patients developed disseminated disease. All patients presented with significant mediastinal lymphadenopathy or abscesses. Seven patients had pulmonary risk factors, including six smokers. The majority of patients had low numbers of neutrophils, monocytes, B cells, CD4+ T cells, and natural killer cells. Other conditions associated with disseminated M. kansasii disease were thymic disorders and IFN-γ/IL-12 defects.

Disseminated M. kansasii disease involving mediastinal lymph nodes is surprisingly common in GATA2 deficiency, but also occurs in defects of IFN-γ synthesis and response. Disseminated M. kansasii should be considered a marker indicating a need to evaluate for immunodeficiency syndromes.

UNASSIGNED

GATA2 deficiency presents with a spectrum of phenotypes including increased susceptibility to viral and bacterial infections, multi-lineage cytopenias, aplastic anemia, leukemic transformation and lymphedema. Allogeneic transplantation is only curative therapy for GATA2 deficiency, but is associated with significant treatment related morbidity and mortality. Given the spectrum of clinical presentation, accurate diagnosis of GATA2 deficiency is necessary to identify patients early in their disease course when allogeneic bone marrow transplantation may be of clinical benefit.

UNASSIGNED

In this report, we present a GATA2 mutation diagnosed in 23-year-old woman presenting with pancytopenia, recurring oral blisters, fatigue and chronic pain. We describe markedly low levels of mature B-cells in the blood and bone marrow and the absence of detectable blood dendritic cells with normal serum immunoglobulin levels and normal numbers of marrow plasma cells. She was ultimately diagnosed with GATA2 haplo-insufficiency due to a GATA2 germ-line mutation and underwent a successful allogeneic bone marrow transplant from a 10/10 HLA matched unrelated donor.

UNASSIGNED

The case illustrates the diagnostic difficulties in identifying GATA2 deficiencies and the importance of family history and genetic testing. GATA2 plays an important role in B-cell and dendritic cell development, and decreased numbers of those cells is a characteristic feature that should prompt consideration of GATA2 deficiency in a patient with pancytopenia. Maturation of B-cells to long-lived plasma cells is relatively unaffected in GATA2 deficiency. Allogeneic stem cell transplantation can correct immune-deficiencies and prevent leukemic transformation in patients with GATA2 deficiency.

Transcription factor (TF)-based reprogramming of somatic tissues holds great promise for regenerative medicine. Previously we demonstrated that the TFs GATA2, GFI1B, and FOS convert mouse and human fibroblasts to hemogenic endothelial-like precursors that generate Hematopoietic Stem Progenitor (HSPC)-like cells over time. This conversion is lacking in robustness both in yield and biological function. Herein, we show that inclusion of GFI1 to the reprogramming cocktail significantly expands the HSPC-like population. AFT024 co-culture imparts functional potential to these cells and allows quantification of stem cell frequency. Altogether, we demonstrate an improved human hemogenic induction protocol that could provide a valuable human in vitro model of hematopoiesis for disease modeling and a platform for cell-based therapeutics.

S100A4 oncoprotein plays a critical role during prostate cancer (CaP) progression and induces immunosuppression in host-tissues. We hypothesized that S100A4 activity in immunosuppressed prostate tumors promotes the growth of neoplastic cells which are likely to become aggressive. In the current study, we investigated if biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive-CaP. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT-response and (ii) high-risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of >1000 CaP patients (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor-survival and metastasis. We show that increased serum-S100A4 levels are associated to the CaP progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of CaP cells and bone-mineralization thus forms an ideal target for therapies for treating CaP. By employing Surface-Plasmon-resonance and ITC, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 antibody-therapy reduced (i) osteoblastic mineralization of bone-derived MSC`s, (ii) S100A4-targets (NFkB/MMP9/VEGF) in CaP-cells, and (iii) TRAMPC2-cell tumorigenicity in an immunosufficient mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased-Stat4+/T-bet+, & decreased-GATA2+/CD68+/CD45+/CD206+ cells), (ii) modulated cytokine-levels in CD4+ve T-cells, and (iii) decreased levels of Interleukin-5/6/12/13, sTNFR1 and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive- CaP in patients.

Erythroid commitment and differentiation are regulated by the coordinated action of a host of transcription factors, including GATA2 and GATA1. Here, we explored GATA-mediated transcriptional regulation through the integrative analysis of gene expression, chromatin modifications, and GATA factors' binding in human multipotent hematopoietic stem/progenitor cells, early erythroid progenitors, and late precursors. A progressive loss of H3K27 acetylation and a diminished usage of active enhancers and super-enhancers were observed during erythroid commitment and differentiation. GATA factors mediate transcriptional changes through a stage-specific interplay with regulatory elements: GATA1 binds different sets of regulatory elements in erythroid progenitors and precursors and controls the transcription of distinct genes during commitment and differentiation. Importantly, our results highlight a pivotal role of promoters in determining the transcriptional program activated upon erythroid differentiation. Finally, we demonstrated that GATA1 binding to a stage-specific super-enhancer sustains the expression of the KIT receptor in human erythroid progenitors.

OBJECTIVE

Myelodysplastic syndromes (MDSs) are rare disorders in children, showing peculiar clinical manifestations and biological features. This review will summarize biological, genetic and clinical features of childhood MDS and will provide an update of the algorithm of treatment of the different disease variants.

RESULTS

The most recent classification of MDS includes refractory cytopenia of childhood (RCC), advanced and therapy-related MDS. Importantly, in children, these clonal hematopoietic disorders may be often associated with inherited bone marrow failure syndromes, this representing a challenge for diagnostic work-up and treatment. Moreover, germline syndromes predisposing to develop MDS/acute myeloid leukemia have been recently identified, such as those caused by mutations in GATA2, ETV6, SRP72 and SAMD9/SAMD9-L.

CONCLUSIONS

Treatment of childhood MDS varies according to specific disease features; allogeneic hematopoietic stem cell transplantation (HSCT) using a Human Leukocyte antigen (HLA)-identical donor, whenever available, represents the treatment of choice for most of these children. HSCT is indicated in MDS with excess of blasts, or in therapy-related MDS. For RCC patients, HSCT is recommended for RCC associated with monosomy 7, or complex karyotype and for patients showing severe neutropenia or transfusion dependence. Novel approaches of HSCT from an HLA-haploidentical relative after selective graft manipulation allow reducing transplant-related complications.

Targeted molecular therapy is the most effective treatment for cancer. An effective therapeutic target for colorectal cancer (CRC) is urgently needed. However, the mechanisms of CRC remain poorly understood, which has hampered research and development of CRC-targeted therapy. TRIM29 is a ubiquitin E3 ligase that has been reported as an oncogene in several human tumors. In this study, we show that increased levels of TRIM29 were detected in CRC compared with normal tissues and were associated with poor clinical outcome, advanced stage and lymph node metastasis, particularly those with right-sided colorectal cancer (RSCC). Notably, GATA2 (GATA Binding Protein 2) transcriptionally repressed TRIM29 expression. The loss of GATA2 and high expression of TRIM29 occur more frequently in RSCC than in left-sided colorectal cancer (LSCC). Functional assays revealed that TRIM29 promotes the malignant CRC phenotype in vitro and in vivo. Mechanistic analyses indicate that TRIM29 promotes pyruvate kinase (mainly PKM1) degradation via the ubiquitin-proteasome pathway. TRIM29 directly targets PKM1 to reduce PKM1/PKM2 ratio, which results in PKM2-mediated aerobic glycolysis (Warburg effect) acting as the dominant energy source in CRC. Our findings suggest that TRIM29 acts as a tumor promoter in CRC, especially in RSCC, and is a potential therapeutic target for CRC treatment.

Keywords: PKM1; TRIM29; colorectal cancer; glucose metabolism; transcriptional regulation.

Embryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase (OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential for blastocyst formation, but whether there is a role for this system at implantation remains unexplored. Here, we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and human trophoblast cells. In an in vitro embryo implantation model, TMG promoted mouse blastocyst breaching of the endometrial epithelium. TMG reduced expression of TE transcription factors Cdx2, Gata2 and Gata3, suggesting that O-GlcNAcylation stimulated TE differentiation to invasive trophoblast. TMG upregulated transcription factors OVOL1 and GCM1, and cell fusion gene ERVFRD1, in a cell line model of syncytiotrophoblast differentiation from human TE at implantation. Therefore O-GlcNAcylation is a conserved pathway capable of driving trophoblast differentiation. TE and trophoblast are sensitive to physical, chemical and nutritive stress, which can occur as a consequence of maternal pathophysiology or during assisted reproduction, and may lead to adverse neonatal outcomes and associated adult health risks. Further investigation of how O-GlcNAcylation regulates trophoblast populations arising at implantation is required to understand how peri-implantation stress affects reproductive outcomes.

Keywords: embryo implantation; extra-embryonic development; implantation failure; protein O-GlcNAcylation; stress; transcription factors; trophoblast differentiation.

Recurrent pregnancy loss (RPL) rates have continued to rise during the last few decades, yet the underlying mechanisms remain poorly understood. An emerging area of interest is the mediation of gene expression by DNA methylation during early pregnancy. Here, genome-wide DNA methylation from placental villi was profiled in both RPL patients and controls. Subsequently, differentially expressed genes were analysed for changes in gene expression. Many significant differentially methylated regions (DMRs) were identified near genes dysregulated in RPL including PRDM1. Differentially expressed genes were enriched in immune response pathways indicating that abnormal immune regulation contributes to RPL. Integrated analysis of DNA methylome and transcriptome demonstrated that the expression level of PRDM1 is fine-tuned by DNA methylation. Specifically, hypomethylation near the transcription start site of PRDM1 can recruit other transcription factors, like FOXA1 and GATA2, leading to up-regulation of gene expression and resulting in changes to trophoblast cell apoptosis and migration. These phenotypic differences may be involved in RPL. Overall, our study provides new insights into PRDM1-dependent regulatory effects during RPL and suggests both a mechanistic link between changes in PRDM1 expression, as well as a role for PRDM1 methylation as a potential biomarker for RPL diagnosis.

Primary myelofibrosis (MF) and secondary MF developing after polycythemia vera or essential thrombocythemia are clonal disorders of hematopoiesis. Currently the only therapy offering the potential of cure is hematopoietic cell transplantation (HCT). Several risk classification systems including clinical, hematological and mutational parameters have been proposed. We analyzed the mutational landscape in addition to the Dynamic International Prognostic Scoring System (DIPSS)-plus in 55 MF patients to determine the combined impact on post-HCT outcome. Mutations, analyzed in 75 genes, were most common in JAK2, CALR, ASXL1, TET2, GATA2, EZH2, U2AF1, and ETV6. Patients with three or more mutations in addition to JAK2 or CALR mutations had a higher post-transplant relapse rate and non-relapse mortality than patients with fewer mutations, independent of DIPSS-plus risk. The presence of higher numbers of mutations identified patients at the highest risk of relapse within the highest overall risk group as determined by DIPSS-plus. These findings are consistent with molecular risk classifications for non-transplanted patients and support the proposed transplant risk classification incorporating mutational information.

Accumulating evidence reveals that hormone leptin, mainly produced by adipocyte, plays a unique role in promotion of liver fibrosis. Hepatic stellate cell (HSC) activation is a key step in liver fibrosis and peroxisome-proliferator activated receptor γ (PPARγ) exerts a crucial role in inhibition of HSC activation. Our previous researches demonstrated that leptin reduced PPARγ1 (a major subtype of PPARγ in HSCs) expression through GATA binding protein 2 (GATA2) binding to a site around -2323 in PPARγ1 promoter. The present researches aimed to examine the effect of GATA3 on leptin-induced inhibition of PPARγ1 and elucidate the relationship between GATA3 and GATA2. Gene expressions were analysed by real-time PCR, western blot, luciferase assay and immunostaining. C57BL/6J ob/ob mouse model of thioacetamide-induced liver injury was used in vivo. Results demonstrate that leptin significantly induces GATA3 expression in HSCs by multiple signalling pathways including NADPH oxidase pathway. There exist crosstalks between NADPH oxidase pathway and the other pathways. GATA3 can bind to GATA2-binding site in PPARγ1 promoter and interacts with GATA2, contributing to leptin inhibition of PPARγ1 expression in HSCs. These data demonstrated novel molecular events for leptin inhibition of PPARγ1 expression in HSCs and thus might have potential implications for clarifying the detailed mechanisms underlying liver fibrosis in diseases in which circulating leptin levels are elevated such as non-alcoholic steatohepatitis in obese patients.

Variation in female reproductive traits, such as fertility, fecundity, and fecundability, are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits have been challenging. Here, we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393, which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a GATA2 binding site in a progesterone-responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage and that the G/A polymorphism arose before the divergence of modern and archaic humans and segregates at intermediate to high frequencies across human populations. Remarkably, the derived A allele is has also been identified in a GWAS as a risk allele for multiple sclerosis. These data suggest that the polymorphism is maintained by antagonistic pleiotropy and a reproduction-health tradeoff in human evolution.

Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor with diverse functions. It has been reported that NR4A1, as a transcriptional activator, is implicated in glucose and lipid metabolism. The aim of this study was to investigate the regulatory role of NR4A1 in adipogenesis and explore the underlying mechanisms. Quantitative real-time PCR and Western blotting were used to analyse the expression of genes involved in synthesis and mobilization of fats in vivo and in vitro. Dual-luciferase reporter assay was conducted to study the regulatory mechanisms of NR4A1. Our data from in vivo study confirmed that NR4A1 knockout (KO) mice fed with high-fat diet were more prone to obesity, and gene expression levels of PPARγ and FAS were increased in KO mice compared to controls; our data from in vitro study showed that NR4A1 overexpression in 3T3-L1 pre-adipocytes inhibited adipogenesis. Moreover, NR4A1 enhanced GATA binding protein 2 (GATA2) expression, which in turn inhibited peroxisome proliferator-activated receptor γ (PPARγ); NR4A1 inhibited sterol regulatory element binding transcription factor 1 (SREBP1) and its downstream gene fatty acid synthase (FAS) by up-regulating p53. NR4A1 inhibits the differentiation and lipid accumulation of adipocytes by enhancing the expression of GATA2 and p53.

Myelodysplastic syndrome is a heterogenous group of disorder with clonal dysregulated hematopoiesis characterized by bone marrow failure, cytogenetic and molecular abnormalities and variable risk of progression to acute myeloid leukemia (AML). The bone marrow niche plays a major role in maintaining the homeostasis and is often injured by the chemotherapeutic drugs leading to catastrophic consequences like myelodysplastic syndrome. In the present study, we made an attempt to find out the osteoblastic niche related alterations in the myelodysplastic bone marrow through mainly flowcytometric and fluorescent microscopic studies. We have also checked the condition of the myelodysplastic bone through micro computed tomography. The results revealed that the affected osteoblasts of the myelodysplastic bone marrow compelled the hematopoietic stem cell to come out of quiescence and become actively proliferating, and in this scenario the decline in expression of cell adhesion molecules like N-Cadherin, Intercellular adhesion molecule 1 (ICAM) and upregulated focal adhesion kinase (FAK) played a major role. The hike in number of osteoclasts in myelodysplastic cases than control also shattered the balance between bone formation and resorption ratio. We have recorded a dysregulated expression of transcription factors GATA2 and CEBPα (CCAAT-enhancer-binding-protein) in the hematopoietic stem progenitor compartment of the myelodysplastic bone marrow, the main reason behind the presence of abnormal myeloblasts in myelodysplastic cases. Collectively, we can say the coordinated perturbations in the osteoblastic niche, cell adhesion molecules together with the transcription factors has resulted in the uncontrolled proliferation of hematopoietic stem cell, dysregulated myelopoiesis, early trafficking of hematopoietic progenitors to blood compartment and at the same time pancytopenic peripheral blood conditions during the progression of N-Ethyl N Nitroso Urea (ENU) induced myelodysplasia.

Keywords: CEBPα; Cell adhesion molecules; GATA2; MDS; N-cadherin; Osteoblastic niche.

OBJECTIVE

Refractory cytopenia of childhood (RCC) is subdivided into myelodysplastic syndrome with multilineage dysplasia (MDS-MLD) and RCC without (w/o) multilineage dysplasia (RCC without MLD). Although RCC is a histomorphological distinct entity, the bone marrow (BM) histology of RCC is not yet characterised in relation to multilineage dysplasia. We investigated the BM histological features of RCC to clarify the characteristics of BM histology of MDS-MLD in childhood compared to RCC without MLD.

RESULTS

The BM histology and cytology in 60 RCC patients from the nationwide registry of Japanese Childhood AA-MDS Study Group were reviewed retrospectively. Although a thorough genetic assessment, including GATA2 and/or SAMD9, was not performed, inherited BM failure disorders were excluded by a cytogenetic test, a chromosome fragility test and a telomere length measurement along with careful clinical assessments. Among the 60 patients, 20 (33%) of MDS-MLD and 40 (67%) of RCC w/o MLD were classified according to their BM cytology. We then investigated the BM histological features and compared them between the two groups. The BM cellularity, distribution pattern of haematopoiesis, frequency of left-shifted granulopoiesis, numbers of micromegakaryocytes and p53 immunostaining-positive cells were significantly different between the groups. The BM histology of MDS-MLD in childhood showed higher cellularity, the more common occurrence of diffuse distribution pattern, more frequently left-shifted granulopoiesis and more micromegakaryocytes and p53 immunostaining-positive cells than RCC without MLD.

CONCLUSIONS

Our results showed that MDS-MLD in childhood had a characteristic BM histology compared to RCC without MLD. The clinical relevance of MDS-MLD in childhood needs to be evaluated.

Cervical cancer is the second most common malignancy and the third reason for mortality among women in developing countries. Although infection by the oncogenic human papilloma viruses is a major cause, genomic contributors are still largely unknown. Network analyses, compared with candidate gene studies, offer greater promise to map the interactions among genomic loci contributing to cervical cancer risk. We report here a differential co-expression network analysis in five gene expression datasets (GSE7803, GSE9750, GSE39001, GSE52903, and GSE63514, from the Gene Expression Omnibus) in patients with cervical cancer and healthy controls. Kaplan-Meier Survival and principle component analyses were employed to evaluate prognostic and diagnostic performances of biomarker candidates, respectively. As a result, seven distinct co-expressed gene modules were identified. Among these, five modules (with sizes of 9-45 genes) presented high prognostic and diagnostic capabilities with hazard ratios of 2.28-11.3, and diagnostic odds ratios of 85.2-548.8. Moreover, these modules were associated with several key biological processes such as cell cycle regulation, keratinization, neutrophil degranulation, and the phospholipase D signaling pathway. In addition, transcription factors ETS1 and GATA2 were noted as common regulatory elements. These genomic biomarker candidates identified by differential co-expression network analysis offer new prospects for translational cancer research, not to mention personalized medicine to forecast cervical cancer susceptibility and prognosis. Looking into the future, we also suggest that the search for a molecular basis of common complex diseases should be complemented by differential co-expression analyses to obtain a systems-level understanding of disease phenotype variability.