Integrated analysis of whole genome and transcriptome sequencing uncovers genetic differences between Zi goose and Xianghai flying goose.

Zi goose is a famous indigenous breed originating from northeast China with high annual egg production. Xianghai flying goose is a composite breed and is bred by crosses of the wild swan goose and the Zi goose. Our previous study revealed significant differences in muscle fiber characteristics between the two populations. Here, we aimed to reveal the underlying genetic basis of the above phenotype differences through whole-genome and transcriptome analysis. A total of 20 blood samples (10 Zi geese and 10 Xianghai flying geese) were used for whole genome sequencing, and eight breast muscle tissue samples (four Zi geese and four Xianghai flying geese) were used for RNA sequencing. Using the FST and XP-EHH analysis, some highly differentiated genome regions annotated with egg production (RORB, WNT4, BMPR1B) and breast muscle development (WNT7B) between the two populations were detected. RNA-sequencing analysis revealed differentially expressed genes related to muscle development (IGF1, PAX7). Moreover, several genes were detected by both genome and transcriptome analysis, and some of them were reported to be associated with muscle growth (SLIT2, PREX1) and intramuscular fat (COL6A1). These findings will help researchers better understand the genetic basis related to egg production and muscle development in geese.

Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice.

This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/ß-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/ß-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc-heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc-mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.

De novo assembly of a wild swan goose (Anser cygnoides) genome.

The swan goose (Anser cygnoides) is the ancestor of the Chinese domestic goose. A previous study reported a scaffold-level genome version for a Chinese indigenous goose breed, and this assembly was used as the swan goose's reference genome. To date, there is still a lack of a chromosome-level genome for the swan goose. Here, we reported a de novo assembly of the genome of a wild swan goose using an integrated strategy that combines Illumina Hiseq, Oxford Nanopore and chromosome conformation capture (Hi-C) sequencing. A total of 134.6 Gb Nanopore data with sequencing coverage of 110.33 and 69.45 Gb Illumina data with coverage of 56.93 were obtained. The genome assembly size was 1153.41 Mb, with a contig N50 of 22.75 Mb. The total size and N50 length of our assembly were larger than the previously reported scaffold-level genome version. In addition, whole-genome sequencing data of 10 geese were mapped to the previous and the current assemblies. On average, 97.88 and 93.18% of the reads were properly mapped and paired into our and the previous assemblies. This high-quality chromosome-level swan goose genome could provide a valuable resource for the utilisation of goose studies and breeding.

Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy.

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN). JMML leukemogenesis is linked to a hyperactivated RAS pathway, with driver mutations in the KRAS, NRAS, NF1, PTPN11, or CBL genes. Previous murine models demonstrated how those genes contributed to the selective hypersensitivity of JMML cells to granulocyte macrophage-colony-stimulating factor (GM-CSF), a unifying characteristic in the disease. However, it is unclear what causes the early death in children with JMML, because transformation to acute leukemia is rare. Here, we demonstrate that loss of Pten (phosphatase and tensin homolog) protein at postnatal day 8 in mice harboring Nf1 haploinsufficiency results in an aggressive MPN with death at a murine prepubertal age of 20 to 35 days (equivalent to an early juvenile age in JMML patients). The death in the mice was due to organ infiltration with monocytes/macrophages. There were elevated activities of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) in cells at physiological concentrations of GM-CSF. These were more pronounced in mice with Nf1 haploinsufficiency than in littermates with wild-type Nf1,but this model is insufficient to cause cells to be GM-CSF hypersensitive. This new model represents a murine MPN model with features of a pediatric unclassifiable mixed MDS/MPN and mimics many clinical manifestations of JMML in terms of age of onset, aggressiveness, and organ infiltration with monocytes/macrophages. Our data suggest that the timing of the loss of PTEN protein plays a critical role in determining the disease severity in myeloid malignancies. This model may be useful for studying the pathogenesis of pediatric diseases with alterations in the Ras pathway.

Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.

ASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80% embryonic lethality. Surviving Asxl1(-/-) mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. Furthermore, Asxl1(-/-) Lin(-)c-Kit(+) cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl1(-/-) mice.

Optimization of Fermented Maize Stover for the Fattening Phase of Geese: Effect on Production Performance and Gut Microflora.

To optimize the utilization of fermented maize stover (FMS) feed during the fattening phase of Xianghai flying geese (XFG), a total of 300 XFG at 125 days of age were randomly assigned to four dietary treatment groups with three replicates of 25 in each set. Group A was fed the basal fattening diet, while the B, C, and D groups were fed the basic fattening diet and diets supplemented with 5%, 10% or 15% FMS, respectively. The findings indicate that the production performance indicators (especially the dressed, eviscerated and breast muscle yield) of Group D closely resembled Group A more than Groups B and C. Intestinal morphometry found that the jejunal villus height and the villus height/crypt depth were significantly increased in Group D compared to Group A. Next, 16S rRNA amplicon sequencing of the extracted DNA revealed that beneficial microbiota (Coprococcus and Victivallis) showed increased abundance in Group D. Cecal flora function analysis further revealed that some amino acid and glycerol biosynthesis were found to be associated with growth performance in geese. These findings suggest that incorporating 15% FMS as a substitute for a portion of the feed during the fattening phase of XFG can effectively sustain their production performance, optimize the gut microbial community and morphometrical traits, provide new insight into using non-conventional feed resources to reduce feed cost and improve economic benefits in the breeding industry.

Potential regulator of meat quality in geese: C1QTNF1 implications on cell proliferation and muscle growth.

Goose creates important economic value depending on their enrich nutrients of meat. Our previous study investigates potential candidate genes associated with variations in meat quality between Xianghai Flying (XHF) Goose and Zi Goose through genomic and transcriptome integrated analysis. Screening of 5 differential expression candidate genes related to muscle development identified by the FST, XP-EHH and RNA-seq in breast muscle from various geese. Among them, C1QTNF1 (C1q and TNF related protein 1), a gene of unknown function in goose, which observed mutations in coding sequence regions in sequencing data. Its function was explored after overexpression and knockdown which designed depending on the genetic sequence of the goose, respectively. Results showed that over-expression of C1QTNF1 significantly enhances cell proliferation and viability. In addition, the expression levels of the fusion marker gene Myomaker and the differentiation marker gene MyoD are significantly upregulated in cells. Knock-down C1QTNF1 leads to down regulated Myomaker and MyoD which involved muscle formation. But, the expression level of muscle atrophy marker MuRF is not significantly changed among different transfection groups. Since protein structures and interactions are closely related to their functions, we further analyzed the C1QTNF1 for physicochemical properties, structural predictions, protein interactions and homology. It can be reasonably inferred that C1QTNF1 has a similar effect to collagen, which may affect muscle development. In summary, we first speculate that C1QTNF1 may play an important regulatory role in muscle growth and development and thereby contributes to the further understanding of the genetic mechanisms that underlie meat quality traits of goose.

Gut microbiota derived from fecal microbiota transplantation enhances body weight of Mimas squabs.

OBJECTIVE: Compared to Mimas pigeons, Shiqi pigeons exhibit greater tolerance to coarse feeding because of their abundant gut microbiota. Here, to investigate the potential of utilizing intestinal flora derived from Shiqi pigeons, the intestinal flora and body indices of Mimas squabs were evaluated after fecal microbiota transplantation (FMT) from donors. METHODS: A total of 90 one-day-old squabs were randomly divided into the control group (CON), the low-concentration group (LC) and the high-concentration group (HC): gavaged with 200 µL of bacterial solution at concentrations of 0, 0.1, and 0.2 g/15 mL, respectively. RESULTS: The results suggested that FMT improved the body weight of Mimas squabs in the HC and LC groups (p<0.01), and 0.1 g/15 mL was the optimal dose during FMT. After 16S rRNA sequencing was performed, compared to those in the CON group, the abundance levels of microflora, especially Lactobacillus, Muribaculaceae, and Megasphaera (p<0.05), in the FMT-treated groups were markedly greater. Random forest analysis indicated that the main functions of key microbes involve pathways associated with metabolism, further illustrating their important role in the host body. CONCLUSION: FMT has been determined to be a viable method for augmenting the weight and intestinal microbiota of squabs, representing a unique avenue for enhancing the economic feasibility of squab breeding.

Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice.

Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignancies. In patients with del(5q) myelodysplastic syndrome (MDS), the transcription factor FOXM1 is frequently downregulated in CD34+ cells. In this study, we demonstrated that Foxm1 haploinsufficiency disturbed normal hematopoiesis and conferred a competitive repopulation advantage for a short period. However, it impaired the long-term self-renewal capacity of hematopoietic stem cells, recapitulating the phenotypes of abnormal hematopoietic stem cells observed in patients with MDS. Moreover, heterozygous inactivation of Foxm1 led to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induced hematopoietic dysplasia in a mouse model with LPS-induced chronic inflammation and accelerated AML-ETO9a-mediated leukemogenesis. We have also identified Parp1, an important enzyme that responds to various types of DNA damage, as a target of Foxm1. Foxm1 haploinsufficiency decreased the ability of HSPCs to efficiently repair DNA damage by downregulating Parp1 expression. Our findings suggest that the downregulation of the Foxm1-Parp1 molecular axis may promote clonal hematopoiesis and reduce genome stability, contributing to del(5q) MDS pathogenesis.

Effects of organic zinc on production performance, meat quality, apparent nutrient digestibility and gut microbiota of broilers fed low-protein diets.

The high cost of feed and nitrogen pollution caused by high-protein diets have become major challenges restricting sustainable development in China's animal husbandry sector. Properly reducing protein levels and improving protein utilization in feed are effective approaches to solving this problem. To determine the optimal dose of methionine hydroxyl analogue chelated zinc (MHA-Zn) in broiler diets with a 1.5% reduction in crude protein (CP), a total of 216 1-day-old broilers were randomly assigned into 4 groups (each group consisted of 3 replications with 18 broilers per replicate), and growth and development indexes were assessed after 42 days. The broilers in control group were fed a basic diet, whereas those in the three test groups were fed diets with a 1.5% reduction in CP. The results showed no significant difference in the edible parts of broilers between low-protein (LP) diet group (90 mg/kg MHA-Zn) and normal diet group (p > 0.05), and adding 90 mg/kg MHA-Zn to LP diet significantly improved ileum morphology and apparent total tract digestibility (ATTD) of nutrient (p < 0.01; p < 0.05). A 16S rRNA sequencing analysis indicated that supplementing the LP diet with 90 mg/kg MHA-Zn was adequate for production performance of broilers and promoted beneficial bacteria in the cecum (Lactobacillus, Butyricoccus, Oscillospira, etc.) (p < 0.01). In summary, adding an optimal dose of organic zinc (90 mg/kg MHA-Zn) in low protein diets led to enhanced production performance of broilers and optimized cecum microbiota. Additionally, the reduction of crude protein consumption in broiler production proved to be a cost-effective measure, while also mitigated nitrogen pollutant emissions in the environment.

miR-375 Induced the Formation and Transgenerational Inheritance of Fatty Liver in Poultry by Targeting MAP3K1.

The liver of poultry is the primary site of lipid synthesis. The excessive production of lipids accumulates in liver tissues causing lipid metabolism disorders, which result in fatty liver disease and have a transgenerational effect of acquired phenotypes. However, its specific mechanisms have not yet been fully understood. In this study, the differentially expressed miR-375 as well as its target gene MAP3K1 (mitogen-activated protein kinase kinase kinase 1) were screened out by interaction network analysis of microRNA sequencing results and transcriptome profiling in the fatty liver group of the F0-F3 generation (p < 0.05 or p < 0.01). Furthermore, the results showed that the number of lipid droplets and triglyceride content were significantly decreased after upregulation of miR-375 in primary hepatocyte culture in vitro (p < 0.05 or p < 0.01). The MAP3K1 knockdown group exhibited the opposite trends (p < 0.05 or p < 0.01). P53, Bcl-x, PMP22, and CDKN2C related to cell proliferation were significantly upregulated or downregulated after knocking down MAP3K1 (p < 0.05). This research uniquely revealed that silencing miR-375 inhibits lipid biosynthesis and promotes cell proliferation, which may be due to the partial regulation of the expression level of MAP3K1, thereby further participating in the transgenerational inheritance process of regulating liver lipid metabolism. These results reveal the pathogenesis of fatty liver in noncoding RNA and provide good candidate genes for breeding progress of disease resistance in chickens.

Comparative Analyses of Production Performance, Meat Quality, and Gut Microbial Composition between Two Chinese Goose Breeds.

Goose meat is consumed by consumers because it contains a relatively high proportion of polyunsaturated fatty acids (PUFAs). This study was conducted to explore the main differences in production performance, breast meat quality traits, and cecal microbiota compositions between the Zi goose (ZG) and Xianghai flying goose (FG). The production performance and breast meat quality trait analyses showed that compared with the ZG, the FG had a higher right breast muscle index, ileum villi height/crypt depth ratio (VH/CD), and cecum fermentation rate (higher short-chain fatty acid (SFCA) concentration); a lower abdominal fat index; a higher proportion of PUFAs; and a lower shear force. Spearman's correlation coefficients between the cecal microbiota composition and production performance indexes suggested that the genus Faecalibacterium was positively associated with production performance; in contrast, the genus Candidatus Saccharimonas was negatively correlated with production performance; moreover, the Ruminococcus torques group, Parasutterella, and Methanobrevibacter were negatively related to the VH/CD. Taken together, in this particular trial, FG had better production performance, healthier meat quality traits, and better intestinal digestion and absorption capacities than ZG. These results not only provide a useful data reference for the production of healthy geese for human consumption but can also help guide the utilization of goose breed resources.

LncRNA RP5-998N21.4 promotes immune defense through upregulation of IFIT2 and IFIT3 in schizophrenia.

Schizophrenia is a complex polygenic disease that is affected by genetic, developmental, and environmental factors. Accumulating evidence indicates that environmental factors such as maternal infection and excessive prenatal neuroinflammation may contribute to the onset of schizophrenia by affecting epigenetic modification. We recently identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA) RP5-998N21.4 by transcriptomic analysis of monozygotic twins discordant for schizophrenia. Importantly, we found that genes coexpressed with RP5-998N21.4 were enriched in immune defense-related biological processes in twin subjects and in RP5-998N21.4-overexpressing (OE) SK-N-SH cell lines. We then identified two genes encoding an interferon-induced protein with tetratricopeptide repeat (IFIT) 2 and 3, which play an important role in immune defense, as potential targets of RP5-998N21.4 by integrative analysis of RP5-998N21.4OE-induced differentially expressed genes (DEGs) in SK-N-SH cells and RP5-998N21.4-coexpressed schizophrenia-associated DEGs from twin subjects. We further demonstrated that RP5-998N21.4 positively regulates the transcription of IFIT2 and IFIT3 by binding to their promoter regions and affecting their histone modifications. In addition, as a general nuclear coactivator, RMB14 (encoding RNA binding motif protein 14) was identified to facilitate the regulatory role of RP5-998N21.4 in IFIT2 and IFIT3 transcription. Finally, we observed that RP5-998N21.4OE can enhance IFIT2- and IFIT3-mediated immune defense responses through activation of signal transducer and activator of transcription 1 (STAT1) signaling pathway in U251 astrocytoma cells under treatment with the viral mimetic polyinosinic: polycytidylic acid (poly I:C). Taken together, our findings suggest that lncRNA RP5-998N21.4 is a critical regulator of immune defense, providing etiological and therapeutic implications for schizophrenia.

Effects of Compound Chinese Herbal Medicine Additive on Growth Performance and Gut Microbiota Diversity of Zi Goose.

This study investigated the effects of CCHMA on growth performance, slaughter performance, serum biochemical indicators, intestinal morphology and microbiota of Zi goose. Initially, it was determined the optimal addition concentration of CCHMA to be 3 g/kg by the first feeding experiment. Then, 78 Zi geese were divided into control and CCHMA supplemented groups. The results showed that the body weight (BW) and average daily gain (ADG) of the CCHMA supplemented group was significantly increased (p < 0.05), and the feed/gain (F/G) of the CCHMA supplemented group was significantly decreased (p < 0.05) compared with the control group. The dressed yield percentage in the CCHMA supplemented group significantly increased by 0.78% (p < 0.05). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly lower in the CCHMA fed birds than in the control group (p < 0.05). Further, 16S rDNA gene sequencing conducted for cecal flora composition found that 3 g/kg CCHMA significantly increased the abundance of beneficial bacteria (CHKCI001, Colidextribacter and Subdoligranulum) (p < 0.05; p < 0.01) and suppressing harmful bacteria (Bacteroidetes and Methanobrevibacter) (p < 0.05) in the cecum of Zi goose. In conclusion, adding 3 g/kg of CCHMA in the diet can improve the growth performance, slaughter performance of Zi goose, and optimize the cecum microflora.

NGS Analysis of Clonality and Minimal Residual Disease in a Patient with Concurrent Richter's Transformation and CLL/SLL.

B-cell lymphomas are neoplastic proliferations of clonal B lymphocytes. Clonality is generally determined by PCR amplification of VDJ rearrangements in the IgH heavy chain or VJ rearrangements in Igκ/Igλ light chain genes followed by capillary electrophoresis. More recently, next-generation sequencing (NGS) has been used to detect clonality in B-cell lymphomas because of the exponential amount of information that is obtained beyond just detecting a clonal population. The additional information obtained is useful for diagnostic confirmation, prognosis assessment, and response to therapy. In this study, we utilized NGS analysis to characterize two histologically distinct lymphomas (DLBCL and CLL/SLL) that were detected contemporaneously in an asymptomatic patient. NGS analysis showed that the same VDJ rearrangement was present in nodal (DLBCL) and marrow (CLL/SLL) biopsies confirming that the DLBCL resulted from Richter's transformation of a subclinical CLL/SLL. The V region of the rearrangement remained unmutated without somatic hypermutation. In silico analysis showed that the HCDR3 sequence was heterogeneous and not stereotypic. Minimal residual disease analysis by NGS showed that the tumor clone decreased by 2.84 logs in the bone marrow after R-CHOP therapy. However, a small number of tumor cells were still detected in the peripheral blood after R-CHOP therapy. Subsequent allogeneic transplantation was successful in eradicating the tumor clone and achieving deep molecular remission. We show that NGS analysis facilitated clinical management in our patient by helping to characterize the VDJ rearrangement in detail and by tracking minimal residual disease with high sensitivity and specificity.

HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia.

Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c+). NPM1c+ maintains a unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c+ controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC, a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c+-associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c+-driven leukemogenesis by rectifying the signature of NPM1c+ leukemic transcription programs. Furthermore, overexpression of HoxBlinc (HoxBlincTg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in (Npm1c/+) mice. HoxBlincTg and Npm1c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c+ signature genes to control their activation in HoxBlincTg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c+ leukemia. HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c+ AML.

A Case of Classic Hodgkin Lymphoma Involving the Uterine Cervix Presenting As Vaginal Spotting.

Classic Hodgkin lymphoma (CHL) is a clonal lymphoid neoplasm derived from B cells. CHL usually involves the lymph nodes. Although cases with extranodal involvement by CHL have been reported, the involvement of the uterine cervix by CHL is an extremely uncommon phenomenon. Herein, we report an unusual case of a 51-year-old female with nodular sclerosis CHL, diagnosed initially via right inguinal lymph node biopsy. After two cycles of chemotherapy, she presented with vaginal spotting and CT scan demonstrated a uterine cervical lesion with hypermetabolic activity. Tissue biopsy sections of the uterine cervix showed cellular infiltrate consisting of large atypical cells including many lacunar cells and occasional Reed-Sternberg cells in the background of mixed reactive cells including small- to medium-sized lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. Immunohistochemical stains show that the large atypical cells are positive for CD30, CD15, MUM-1, and weakly positive for PAX-5. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) is negative. The morphological and immunohistochemical findings were consistent with involvement by nodular sclerosis CHL. This case demonstrates a rare presentation of CHL that may pose a diagnostic problem if its existence is not considered in the differential diagnosis. Furthermore, we reviewed the literature and only found two previous publications described uterine cervix involvement by CHL. Although it is very rare, CHL involvement should be included in the differential diagnosis and an appropriate work-up should be performed to evaluate CHL involvement of cervix when patients with CHL present with signs or symptoms suggesting a cervical lesion.

Presentation of a diagnostically challenging case of chronic eosinophilic leukemia with marrow dysplasia and ringed sideroblasts.

Chronic eosinophilic leukemia, not otherwise specified can be challenging to differentiate from hypereosinophilic syndrome and myelodysplastic syndromes with elevated eosinophilia. We present a diagnostically challenging case of chronic eosinophilic leukemia, not otherwise specified that initially seemed like a myelodysplastic syndrome but progressed to eosinophilic tissue infiltration and overt eosinophilic dyspoiesis. In addition, we discuss the morphologic and molecular findings that can overlap among these entities that made the diagnosis difficult in the case presented.

Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway.

Leukemia stem cells (LSCs) are the rare populations of acute myeloid leukemia (AML) cells that are able to initiate, maintain, and propagate AML. Targeting LSCs is a promising approach for preventing AML relapse and improving long-term outcomes. While Slug, a zinc-finger transcription repressor, negatively regulates the self-renewal of normal hematopoietic stem cells, its functions in AML are still unknown. We report here that Slug promotes leukemogenesis and its loss impairs LSC self-renewal and delays leukemia progression. Mechanistically, Slc13a3, a direct target of Slug in LSCs, restricts the self-renewal of LSCs and markedly prolongs recipient survival. Genetic or pharmacological inhibition of SLUG or forced expression of Slc13a3 suppresses the growth of human AML cells. In conclusion, our studies demonstrate that Slug differentially regulates self-renewal of LSCs and normal HSCs, and both Slug and Slc13a3 are potential therapeutic targets of LSCs.