A metagenomics study reveals the gut microbiome as a sex-specific modulator of healthy aging in Hainan centenarians.

BACKGROUND: Sex differences in health status and life expectancy are widely accepted to exist. The mechanisms underlying it are still poorly understood. In this study, we aimed to clarify the influences and contributions of sex on the gut microbiome in healthy centenarians and to explore the different roles played by the gut microbiome in healthy aging between the sexes. RESULTS: Taking covariates of different dimensions into account (social demographics, anthropometry, the activities of daily living, dietary structure, mental state, blood tests, lifestyle and disease history), our data showed that sex was one of the most significant covariates affecting the gut microbiome of healthy centenarians at both the species and Kyoto Encyclopedia of Genes and Genomes Orthology (KO) levels. The beta diversity between the sexes were significantly different (Adonis test: p = 0.011, R2 = 0.031), and the male centenarians had a greater alpha diversity than the females (Simpson and Shannon test: P<0.05). At the species level, we identified 31 species enriched in males and 7 species enriched in females. The composition and function patterns of the microbiome varied between the sexes. Further functional analysis showed that males' gut microbiome exhibited greater resistance to oxidative stress compared to females. In contrast to men, the species associated with healthy aging dominated among healthy female centenarians, while the species associated with unhealthy aging were relatively rare. CONCLUSIONS: The present study reveals that the gut microbiome structure and resistance to oxidative stress in healthy centenarians differ between the sexes and provides new insights into the possible sex-specific role of the gut microbiome in healthy aging.

Hereditary hemorrhagic telangiectasia involving portal venous system: A case report and review of the literature.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 in the general population. It is characterized by vasodilation, which affects specific organs, such as the skin, mucous membranes, brain, lungs, gastrointestinal tract, liver, and others. However, HHT rarely involves the portal venous system to cause serious clinical complications. CASE SUMMARY: A 68-year-old woman was admitted to the emergency department due to four consecutive days of abdominal pain and bloody stool and was subsequently diagnosed with HHT. Computed tomography angiography confirmed the presence of an arteriovenous fistula (AVFs). Considering this specific manifestation, whole exome sequencing was performed. After a comprehensive evaluation, a selective superior mesenteric artery embolization was prioritized to avoid intestinal ischemia. The postoperative symptoms of the patient were quickly relieved. Unfortunately, two months post-procedure the patient died from intestinal necrosis and abdominal infection related to remaining AVFs. CONCLUSION: For patients with diffuse superior mesenteric AVFs, selective mesenteric arterial embolization may lead to positive short-term outcomes.

Clinical characteristics of patients with early-onset diabetes mellitus: a single-center retrospective study.

BACKGROUND: The prevalence of diabetes mellitus (DM) is dramatically increasing around the world, and patients are getting younger with changes in living standards and lifestyle. This study summarized and analyzed the clinical characteristics of different types of newly diagnosed diabetes mellitus patients with an onset age between 18 and 40 years to provide clinical evidence for the early diagnosis and treatment of diabetes, reduce short-term and long-term complications and offer scientific and personalized management strategies. METHODS: A total of 655 patients newly diagnosed with early-onset diabetes mellitus in the Department of Endocrinology, the First Medical Center of PLA General Hospital from January 2012 to December 2022 were retrospectively enrolled in this study, with an onset age of 18-40 years. Their clinical data were collected and investigated. All patients were divided into two groups according to whether they presented with diabetic microangiopathy. Similarly, patients with early-onset type-2 diabetes were grouped in accordance with whether they had ketosis at the time of diagnosis. Binary logistic regression analysis was performed to analyze risk factors, and receiver-operating characteristic (ROC) analysis was used to explore the predictive value of significant risk factors. RESULTS: The findings were as follows: (1) Of 655 enrolled patients, 477 (72.8%) were male and 178 (27.1%) were female, with a mean age of onset of was 29.73 years ± 0.24 SD. (2) The prevalence of early-onset diabetes was gradually increasing. Type-2 diabetes was the most common type of early-onset diabetes (491, 75.0%). The ages of onset of early-onset type-1 diabetes, type-2 diabetes and LADA were mainly 18-24 years, 25-40 years and 33-40 years, respectively. (3) Initial clinical manifestations of early-onset diabetes were classic diabetes symptoms (361, 55.1%), followed by elevated blood glucose detected through medical examination (207, 31.6%). (4) Binary logistic regression analysis suggested that high serum uric acid (UA), a high urinary albumin-to-creatinine ratio (UACR) and diabetic peripheral neuropathy (DPN) were risk factors for microangiopathy in early-onset diabetes patients (P < 0.05). The area under the curve (AUC) on ROC analysis of the combination of UA, UACR and DPN was 0.848, 95% CI was 0.818 ~ 0.875, sensitivity was 73.8% and specificity was 85.9%, which had higher predictive value than those of UA, UACR and DPN separately. (5) Weight loss, high glycosylated hemoglobin (HbA1c) and young onset age were risk factors for ketosis in patients with early-onset type-2 diabetes (P < 0.05). CONCLUSION: (1) Men were more likely to have early-onset diabetes than women. (2) Early-onset diabetes patients with high serum uric acid levels, high UACRs and peripheral neuropathy were prone to microangiopathy. Comprehensive evaluation of these risk factors could have higher predictive value in the prediction, diagnosis and treatment of microvascular lesions. (3) Patients with weight loss at onset, high HbA1c and young onset age were more likely to develop ketosis. Attention should be given to the metabolic disorders of these patients.

Efficacy and safety of Oral LL-37 against the Omicron BA.5.1.3 variant of SARS-COV-2: A randomized trial.

Recombinant LL-37 Lactococcus lactis (Oral LL-37) was designed to prevent progression of COVID-19 by targeting virus envelope, however, effectiveness and safety of Oral LL-37 in clinical application was unclear. A total of 238 adult inpatients, open-labelled, randomized, placebo-controlled, single-center study was conducted to investigate the primary end points, including negative conversion time (NCT) of SARS-CoV-2 RNA and adverse events (AEs). As early as intervened on 6th day of case confirmed, Oral LL-37 could significantly shorten NCT (LL-37 9.80 ± 2.67 vs. placebo 14.04 ± 5.89, p < 0.01). For Oral LL-37, as early as treated in 6 days, the adjusted hazard ratio (HR) for a primary event of nucleic acid negative outcome was 6.27-fold higher than 7-day-later (HR: 6.276, 95% confidence interval [CI]: 3.631-10.848, p < 0.0001), and the adjusted HR of Oral LL-37 within 6 days is higher than placebo (HR: 2.427 95% CI: 1.239-4.751, p = 0.0097). No severe AEs were observed during hospitalization and follow-up investigation. This study shows that early intervention of Oral LL-37 incredibly reduces NCT implying a potential for clearance of Omicron BA.5.1.3 without evident safety concerns.

Lactobacillus oris improves non-alcoholic fatty liver in mice and inhibits endogenous cholesterol biosynthesis.

We previously confirmed that a strain of Lactobacillus oris isolated from the fecal samples of healthy Hainan centenarian having potent lipid-lowering ability in HepG2 cells; and this study was to investigate the effect of the stain on non-alcoholic fatty liver in mice in vivio. The Lactobacillus oris strain isolated from Hainan centenarian fecal samples were frozen stored in our laboratory. Thirty ob/ob mice (10 in each group) were orally gavaged with Lactobacillus oris (Lactobacillus, 5 × 109 cfu), mixed probiotics (Mixed, 5 × 109 cfu, a mixture with known lipid-lowering ability), or culture medium (Control) respectively. Lactobacillus oris isolated from fecal samples of Hainan centenarians showed significantly in vivo lipid lowering ability compared with the controls, and the ability was comparable with mixed probiotics strains in mice The possible mechanisms of lipid-lowering of probiotics and Lactobacillus oris may be associated with HMGR inhibition to suppress the synthesis of endogenous cholesterol; bile acids reabsorption, and intestinal FXR-FGF15 signaling pathways promoting the cholesterol conversion into bile acids secretion.

RNA-Seq Analysis Reveals Altered Expression of Cell Adhesion-Related Genes Following PZR Knockout in Lung Cancer Cells.

Protein zero related (PZR) serves as a substrate and anchor protein for SHP-2, the product of the proto-oncogene PTPN11 that is frequently mutated in cancers. The expression level of PZR is elevated in various cancers, which is correlated with an unfavorable prognosis. The role of PZR in lung cancer is not fully studied. To investigate how PZR affects signaling pathways involved in LUAD development, we utilized the CRISPR technology to knock out PZR expression in SPC-A1 lung adenocarcinoma cells and then conducted RNA sequencing to profile the transcriptome. Our results showed that 226 genes exhibited differential expressions in PZR-knockout SPC-A1 cells vs wild-type cells. Many of the genes encode proteins involved in cell adhesion, migration, actin cytoskeleton organization, and regulation of cell shape. Furthermore, our experimental data showed that PZR-knockout SPC-A1 cells displayed faster attachment to tissue culture dishes and slower detachment from the dishes upon EDTA treatment. The data suggest an important role of PZR in cell-matrix interaction and may provide new insights into the signaling events that regulate cancer development.

miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3' untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.

PZR promotes tumorigenicity of lung cancer cells by regulating cell migration and invasion via modulating oxidative stress and cell adhesion.

PZR is a transmembrane glycoprotein encoded by the MPZL1 gene. It serves as a specific binding protein and substrate of tyrosine phosphatase SHP-2 whose mutations cause developmental diseases and cancers. Bioinformatic analyses of cancer gene databases revealed that PZR is overexpressed in lung cancer and correlated with unfavorable prognosis. To investigate the role of PZR in lung cancer, we employed the CRISPR technique to knockout its expression and recombinant lentiviruses to overexpress it in lung adenocarcinoma SPC-A1 cells. While knockout of PZR reduced colony formation, migration, and invasion, overexpression of PZR had the opposite effects. Furthermore, when implanted in immunodeficient mice, PZR-knockout SPC-A1 cells showed suppressed tumor-forming ability. Finally, the underlying molecular mechanism for these functions of PZR is its positive role in activating tyrosine kinases FAK and c-Src and in maintaining the intracellular level of reactive oxygen species (ROS). In conclusion, our data indicated that PZR plays an important role in lung cancer development, and it may serve as a therapeutic target for anti-cancer development and as a biomarker for cancer prognosis.

Sunitinib selectively targets leukemogenic signaling of mutant SHP2 in juvenile myelomonocytic leukemia.

Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a hematopoietic malignancy with poor response to cytotoxic chemotherapy. Novel therapeutic strategies are urgently needed for patients with JMML. Previously, we established a novel cell model of JMML with HCD-57, a murine erythroleukemia cell line that depends on EPO for survival. SHP2-D61Y or -E76K drove the survival and proliferation of HCD-57 in absence of EPO. In this study, we identified sunitinib as a potent compound to inhibit SHP2-mutant cells by screening a kinase inhibitor library with our model. We used cell viability assay, colony formation assay, flow cytometry, immunoblotting, and a xenograft model to evaluate the effect of sunitinib against SHP2-mutant leukemia cells in vitro and in vivo. The treatment of sunitinib selectively induced apoptosis and cell cycle arrest in mutant SHP2-transformed HCD-57, but not parental cells. It also inhibited cell viability and colony formation of primary JMML cells with mutant SHP2, but not bone marrow mononuclear cells from healthy donors. Immunoblotting showed that the treatment of sunitinib blocked the aberrantly activated signals of mutant SHP2 with deceased phosphorylation levels of SHP2, ERK, and AKT. Furthermore, sunitinib effectively reduced tumor burdens of immune-deficient mice engrafted with mutant-SHP2 transformed HCD-57. Our data demonstrated that sunitinib selectively inhibited SHP2-mutant leukemia cells, which could serve as an effective therapeutic strategy for SHP2-mutant JMML in the future.

SHP2 participates in decidualization by activating ERK to maintain normal nuclear localization of progesterone receptor.

In brief: The establishment and maintenance of embryo implantation and pregnancy require decidualization of endometrial stromal cells. This paper reveals that SHP2 ensures the correct subcellular localization of progesterone receptor, thereby safeguarding the process of decidualization. Abstract: Decidualization is the process of conversion of endometrial stromal cells into decidual stromal cells, which is caused by progesterone production that begins during the luteal phase of the menstrual cycle and then increases throughout pregnancy dedicated to support embryonic development. Decidualization deficiency is closely associated with various pregnancy complications, such as recurrent miscarriage (RM). Here, we reported that Src-homology-2-containing phospho-tyrosine phosphatase (SHP2), a key regulator in the signal transduction process downstream of various receptors, plays an indispensable role in decidualization. SHP2 expression was upregulated during decidualization. SHP2 inhibitor RMC-4550 and shRNA-mediated SHP2 reduction resulted in a decreased level of phosphorylation of ERK and aberrant cytoplasmic localization of progesterone receptor (PR), coinciding with reduced expression of IGFBP1 and various other target genes of decidualization. Solely inhibiting ERK activity recapitulated these observations. Administration of RMC-4550 led to decidualization deficiency and embryo absorption in mice. Moreover, reduced expression of SHP2 was detected in the decidua of RM patients. Our results revealed that SHP2 is key to PR's nuclear localization, thereby indispensable for decidualization and that reduced expression of SHP2 might be engaged in the pathogenesis of RM.

Knockdown of phosphatases of regenerating liver-1 prolongs the lifespan of Caenorhabditis elegans via activating DAF-16/FOXO.

Phosphatases of regenerating liver (PRLs) are dual-specificity protein phosphatases. The aberrant expression of PRLs threatens human health, but their biological functions and pathogenic mechanisms are unclear yet. Herein, the structure and biological functions of PRLs were investigated using the Caenorhabditis elegans (C. elegans). Structurally, this phosphatase in C. elegans, named PRL-1, consisted of a conserved signature sequence WPD loop and a single C(X)5 R domain. Besides, by Western blot, immunohistochemistry and immunofluorescence staining, PRL-1 was proved to mainly express in larval stages and express in intestinal tissues. Afterward, by feeding-based RNA-interference method, knockdown of prl-1 prolonged the lifespan of C. elegans but also improved their healthspan, such as locomotion, pharyngeal pumping frequency, and defecation interval time. Furthermore, the above effects of prl-1 appeared to be taken without acting on germline signaling, diet restriction pathway, insulin/insulin-like growth factor 1 signaling pathway, and SIR-2.1 but through a DAF-16-dependent pathway. Moreover, knockdown of prl-1 induced the nuclear translocation of DAF-16, and upregulated the expression of daf-16, sod-3, mtl-1, and ctl-2. Finally, suppression of prl-1 also reduced the ROS. In conclusion, suppression of prl-1 enhanced the lifespan and survival quality of C. elegans, which provides a theoretical basis for the pathogenesis of PRLs in related human diseases.

Bioinformatics analyses of combined databases identify shared differentially expressed genes in cancer and autoimmune disease.

BACKGROUND: Inadequate immunity caused by poor immune surveillance leads to tumorigenesis, while excessive immunity due to breakdown of immune tolerance causes autoimmune genesis. Although the function of immunity during the onset of these two processes appears to be distinct, the underlying mechanism is shared. To date, gene expression data for large bodies of clinical samples are available, but the resemblances of tumorigenesis and autoimmune genesis in terms of immune responses remains to be summed up. METHODS: Considering the high disease prevalence, we chose invasive ductal carcinoma (IDC) and systemic lupus erythematosus (SLE) to study the potential commonalities of immune responses. We obtained gene expression data of IDC/SLE patients and normal controls from five IDC databases (GSE29044, GSE21422, GSE22840, GSE15852, and GSE9309) and five SLE databases (GSE154851, GSE99967, GSE61635, GSE50635, and GSE17755). We intended to identify genes differentially expressed in both IDC and SLE by using three bioinformatics tools including GEO2R, the limma R package, and Weighted Gene Co-expression Network Analysis (WGCNA) to perform function enrichment, protein-protein network, and signaling pathway analyses. RESULTS: The mRNA levels of signal transducer and activator of transcription 1 (STAT1), 2'-5'-oligoadenylate synthetase 1 (OAS1), 2'-5'-oligoadenylate synthetase like (OASL), and PML nuclear body scaffold (PML) were found to be differentially expressed in both IDC and SLE by using three different bioinformatics tools of GEO2R, the limma R package and WGCNA. From the combined databases in this study, the mRNA levels of STAT1 and OAS1 were increased in IDC while reduced in SLE. And the mRNA levels of OASL and PML were elevated in both IDC and SLE. Based on Kyoto Encyclopedia of Genes and Genomes pathway analysis and QIAGEN Ingenuity Pathway Analysis, both IDC and SLE were correlated with the changes of multiple components involved in the Interferon (IFN)-Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. CONCLUSION: The expression levels of STAT1 and OAS1 manifest the opposite expression tendency across cancer and autoimmune disease. They are components in the IFN-JAK-STAT signaling pathway related to both tumorigenesis and autoimmune genesis. STAT1 and OAS1-associated IFN-JAK-STAT signaling could explain the commonalities during tumorigenesis and autoimmune genesis and render significant information for more precise treatment from the point of immune homeostasis.

Leukemogenic SHP2 mutations lead to erythropoietin independency of HCD-57 cells: a novel model for preclinical research of SHP2-mutant JMML.

Leukemogenic SHP2 mutations occur in 35% of patients with juvenile myelomonocytic leukemia (JMML), a rare but fatal hematopoietic malignancy without representative cell models, which are urgently needed to investigate the pathogenesis and to develop novel therapeutic strategies. In this study, we established stable cell lines with aberrant signaling resembling SHP2-mutant JMML through retroviral expression of SHP2-D61Y/E76K in HCD-57 cells, a murine erythroleukemia cell line that depends on erythropoietin (EPO) for survival. SHP2-D61Y/E76K drives the survival and proliferation of HCD-57 cells in the absence of EPO, but not in Ba/F3 cells in the absence of IL-3. Transformed HCD-57 cells showed activated MAPK signaling that is consistent with SHP2-mutant JMML. Transformed HCD-57 cells were sensitive to dasatinib and trametinib, two targeted drugs previously reported to inhibit SHP2-mutant JMML cells. Furthermore, we injected mutant SHP2-transformed HCD-57 cells into immune-deficient mice intravenously and found that these cells rapidly proliferated in the spleen and bone marrow, providing an excellent model for in vivo testing of drugs targeting the aberrant signaling of mutant SHP2. In conclusion, we established the novel cell lines HCD-57/SHP2-E76K and -D61Y that depended on signaling of mutant SHP2 for survival, thus resembling SHP2-mutant JMML. Our model is a valuable tool to investigate the pathogenic mechanisms of mutant SHP2 and targeted drugs for SHP2-mutant JMML.

A bibliometric and visual analysis of the use of ustekinumab in Crohn's disease using CiteSpace.

Background: The novel biologic agent ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin-12 and interleukin-23, has been applied in the treatment of Crohn's disease (CD). With the development of relevant research, the clinical treatment and favorable prognosis of UST in CD have garnered considerable attention. However, there is a lack of reports that present the current status of UST-related studies in a comprehensive and objective manner. Consequently, this study aims to visually analyze the current status and clinical trends of UST-related research, identify leading researchers, and recognize deficiencies using bibliometrics and knowledge mapping, which might assist in understanding future research priorities in that specific field. Methods: Published articles containing the use of UST in CD were retrieved from the Web of Science core collection database between 2008 and 2022. Then, the bibliometric analysis was performed, and a knowledge map was generated and visualized using the CiteSpace software. Results: A total of 479 articles published between 2008 and 2022 were included in the bibliometric analysis. These publications were authored by 185 scholars from 51 countries or regions, among which the United States (38.3%), Canada (16.9%) and England (10.0%) were predominant in publishing. The keyword analysis indicated that UST has long been a popular biologic agent, and its clinical efficacy, safety, and indication for vulnerable populations in CD are popular research topics. The phrase "fecal calprotectin," a biomarker reflecting the degree of disease activity and monitoring the therapeutic response, began to gain traction in 2020 and has continued to this day. Looking for UST-related biomarkers was gaining clinical attention. Conclusion: The number of clinical studies involving the outcome of UST treatment in CD patients has increased, with the current research focusing on efficacy, safety, indications for vulnerable populations, therapeutic drug monitoring, and biomarkers. As an alternative drug after the failure of traditional immunosuppressive therapies or TNF-α antagonist therapy, UST is an effective and safe therapy in real-world refractory CD patients. UST will remain an active candidate for research in the treatment of CD.

Efficacy of SCF drug conjugate targeting c-KIT in gastrointestinal stromal tumor.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare type of cancer that occurs in the gastrointestinal tract. The majority of GIST cases carry oncogenic forms of KIT, the receptor for stem cell factor (SCF). Small molecule kinase inhibitor imatinib is effective in prolonging the survival of GIST patients by targeting KIT. However, drug resistance often develops during the therapeutic treatment. Here, we produced a SCF-emtansine drug conjugate (SCF-DM1) with favorable drug efficacy towards GIST cells. METHODS: Recombinant human SCF (rhSCF) was expressed in E. coli cells and further purified with Ni-NTA Sepharose and Phenyl Sepharose. It was then conjugated with DM1, and the conjugated product SCF-DM1 was evaluated using in vitro cell-based assays and in vivo xenograft mouse model. RESULTS: SCF-DM1 was effective in inhibiting imatinib-sensitive and -resistant GIST cell lines and primary tumor cells, with IC50 values of < 30 nM. It induced apoptosis and cell cycle arrest in GIST cells. In xenograft mouse model, SCF-DM1 showed favorable efficacy and safety profiles. CONCLUSIONS: rhSCF is a convenient and effective vector for drug delivery to KIT positive GIST cells. SCF-DM1 is an effective drug candidate to treat imatinib-sensitive and -resistant GIST.

HMGA1 chromatin regulators induce transcriptional networks involved in GATA2 and proliferation during MPN progression.

Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression.

Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies.

Platelets are essential components in the tumor microenvironment. For decades, clinical data have demonstrated that cancer patients have a high risk of thrombosis that is associated with adverse prognosis and decreased survival, indicating the involvement of platelets in cancer progression. Increasing evidence confirms that cancer cells are able to induce production and activation of platelets. Once activated, platelets serve as allies of cancer cells in tumor growth and metastasis. They can protect circulating tumor cells (CTCs) against the immune system and detachment-induced apoptosis while facilitating angiogenesis and tumor cell adhesion and invasion. Therefore, antiplatelet agents and platelet-based therapies should be developed for cancer treatment. Here, we discuss the mechanisms underlying the bidirectional cancer-platelet crosstalk and platelet-based therapeutic approaches.