HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia.

HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CCCTC-binding factor (CTCF) chromatin boundaries and regulates CTCF-mediated genome topology remains unknown. Here, we show that HOTTIP directly interacts with and regulates a fraction of CTCF-binding sites (CBSs) in the AML genome by recruiting CTCF/cohesin complex and R-loop-associated regulators to form R-loops. HOTTIP-mediated R-loops reinforce the CTCF boundary and facilitate formation of TADs to drive gene transcription. Either deleting CBS or targeting RNase H to eliminate R-loops in the boundary CBS of ß-catenin TAD impaired CTCF boundary activity, inhibited promoter/enhancer interactions, reduced ß-catenin target expression, and mitigated leukemogenesis in xenograft mouse models with aberrant HOTTIP expression. Thus, HOTTIP-mediated R-loop formation directly reinforces CTCF chromatin boundary activity and TAD integrity to drive oncogene transcription and leukemia development.

Effect of prior lenalidomide or daratumumab exposure on hematopoietic stem cell collection and reconstitution in multiple myeloma.

BACKGROUND: The roles of Lenalidomide (Len) and Daratumumab (Dara) in multiple myeloma treatment are well-established, yet their influences on hematopoietic stem cell harvesting and reconstitution remain disputed. METHODS: We conducted a systematic database review to identify cohort studies or RCTs evaluating the effect of the use of Len or Dara on hematopoietic stem cell collection and peripheral blood count recovery in multiple myeloma patients. Effects on hematopoietic collection or reconstitution were estimated by comparing standardized mean differences (SMD) and mean differences (MD), or median differences. RESULTS: Eighteen relevant studies were identified, summarizing mobilization results. For Len, data from 13 studies were summarized, including total CD34+ cell yield, collection failure rate, and time to neutrophil and platelet engraftment. Results indicated that Len exposure led to decreased stem cell collection [SMD=-0.23, 95% CI (-0.34, -0.12)]. However, collection failure (<2×106) could be mitigated by plerixafor [OR=2.14, 95% CI (0.96, 4.77)]. For Dara, two RCTs and three cohort studies were included, showing that Dara exposure resulted in a reduction in total stem cells even with optimized plerixafor mobilization [SMD=-0.75, 95% CI (-1.26, -0.23)], and delayed platelet engraftment recovery [MD=1.20, 95% CI (0.73, 1.66)]. CONCLUSIONS: Our meta-analysis offers a comprehensive view of Len and Dara's impacts on hematopoietic stem cell collection and reconstitution in multiple myeloma. Len usage could lead to reduced stem cell collection, counteracted by plerixafor mobilization. Dara usage could result in diminished stem cell collection and delayed platelet engraftment.

ARMOR: Auto-Assembled Resilient Biomimetic Calcified Ornaments for Selective Cell Protection by Dual-Aptamer-Driven Hybridization Chain Reaction.

Unlike plant and microbial cells having cell walls, the outermost layer of mammalian cell is a delicate, two-layered structure of phospholipids with proteins embedded, which is susceptible to environmental changes. It is necessary to create an "armor" on cell surface to protect cell integrity. Here, we propose an Auto-assembled Resilient bioMimetic calcified ORnaments (ARMOR) strategy driven by dual-aptamer-based hybridization chain reaction (HCR) and Ca2+ assisted calcification for selective cell protection. This co-recognition design enhances the selectivity and leverages robust in situ signal amplification by HCR to improve the sensitivity. The calcified shell is cogenerated by crosslinking the alginate-HCR product with Ca2+ ion. ARMOR has high efficiency for shielding cells from environmental assaults, which can be applied to circulating tumor cell (CTC) protection, isolation, and identification, maintaining the native state and intact genetic information for downstream analysis.

A Multifunctional Liquid Crystal as Hole Transport Layer Additive Enhances Efficiency and Stability of Perovskite Solar Cells.

Lithium bis(trifluoromethanesulfonyl)imide (Li-TFSI) has been identified as the most used and effective p-dopant for hole transport layer (HTL) in perovskite solar cells (PSCs). However, the migration and agglomeration of Li-TFSI in HTL negatively impact PSCs performance and stability. Herein, we report an effective strategy for adding a liquid crystal organic small molecule (LQ) into Li-TFSI doped (2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'- spirobifluorene (Spiro-OMeTAD) HTL. It was found that the introduction of LQ into Spiro-OMeTAD HTL can efficiently enhance the charge carrier extraction and transportation in device, which can strongly retard the charge carrier recombination in device. Consequently, the PSCs efficiency is significantly enhanced to 24.42 % (Spiro-OMeTAD+LQ) from 21.03 % (Spiro-OMeTAD). The chemical coordination between LQ and Li-TFSI can strongly confine Li+ ions migration and agglomeration of Li-TFSI, thus, achieving the enhanced device stability. Only a 9 % efficiency degradation is observed for un-encapsulated device prepared with Spiro-OMeTAD and LQ after 1700 h under air environment, while the efficiency drops by 30 % for the reference device. This work provides an effective strategy for improving the efficiency and stability of PSCs, and gives some important insights for understanding intrinsic hot carriers dynamics for perovskite-based optoelectronic devices.

Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients.

BACKGROUND: Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. METHODS: Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. RESULTS: The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. CONCLUSIONS: These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

Alteration of CTCF-associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis.

Aberrant activation of the TAL1 is associated with up to 60% of T-ALL cases and is involved in CTCF-mediated genome organization within the TAL1 locus, suggesting that CTCF boundary plays a pathogenic role in T-ALL. Here, we show that -31-Kb CTCF binding site (-31CBS) serves as chromatin boundary that defines topologically associating domain (TAD) and enhancer/promoter interaction required for TAL1 activation. Deleted or inverted -31CBS impairs TAL1 expression in a context-dependent manner. Deletion of -31CBS reduces chromatin accessibility and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter-1 leading to inhibition of TAL1 expression in erythroid cells, but not T-ALL cells. However, in TAL1-expressing T-ALL cells, the leukemia-prone TAL1 promoter-IV specifically interacts with the +19 stem cell enhancer located 19 Kb downstream of TAL1 and this interaction is disrupted by the -31CBS inversion in T-ALL cells. Inversion of -31CBS in Jurkat cells alters chromatin accessibility, histone modifications and CTCF-mediated TAD leading to inhibition of TAL1 expression and TAL1-driven leukemogenesis. Thus, our data reveal that -31CBS acts as critical regulator to define +19-enhancer and the leukemic prone promoter IV interaction for TAL1 activation in T-ALL. Manipulation of CTCF boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.

A Retrospective Study of Percutaneous Balloon Kyphoplasty for the Treatment of Symptomatic Schmorl's Nodes: 5-Year Results.

BACKGROUND Despite literature supporting the efficiency of percutaneous balloon kyphoplasty (PKP) in treating osteoporotic and malignant vertebral compression fractures, few reports exist that document its use for treatment of symptomatic Schmorl's nodes (SNs) refractory to conservative treatment. Patients with symptomatic SNs could have pain in the vertebrae similar to an acute vertebral compression fracture. MRI is very helpful in diagnosing symptomatic SNs when x-ray and CT scan are unremarkable. In painful cases, the vertebrae bone marrow around the SNs is hyperintense on T2-weighted subsequence. We evaluated the long-term safety and effectiveness of PKP for the treatment of symptomatic SNs not responding to conservative therapy. MATERIAL AND METHODS From January 2008 to December 2012, 32 patients suffering from symptomatic SNs underwent 43 PKP procedures. Outcome data, including mean height ratio of anterior and middle vertebral body, Visual Analog Scale (VAS score) for pain measurement, Oswestry Disability Indexes (ODI score) and SF-36 questionnaires for function measurement were recorded preoperatively, postoperatively, and at one month, six months, two years, and five years after treatment. RESULTS Thirty-two patients were treated successfully with PKP. Clinically asymptomatic cement leakage was observed in three (6.98%) of the treated vertebral bodies. The mean height ratio of anterior and middle vertebral bodies changed from 98.2±1.6% preoperatively to 98.5±1.4% postoperatively (p>0.05) and 98.3±1.5% preoperatively to 98.8±1.9% postoperatively (p>0.05). The mean VAS scores, ODI score, and SF-36 scores for physical function (PF), bodily pain (BF), social functioning (SF), and vitality (VT) all showed significant improvements (p<0.05). During the 5-year follow-up, the stabilization of the height of the vertebral body and functional improvements were all maintained. CONCLUSIONS PKP is a safe and effective procedure for the treatment of symptomatic SNs refractory to conservative therapy.

[Expression and function of ECRG4 in hepatocellular carcinoma].

OBJECTIVE: To investigate the expression of esophageal cancer related gene 4 (ECRG4) in human hepatocellular carcinoma and the role of ECRG4 in proliferation, apoptosis and migration of hepatoma cells. METHODS: ECRG4 expression was investigated in normal or tumor liver cell lines including QSG7701 and HepG2 cells, and in 24 pairs of fresh samples of hepatocellular carcinoma by quantitative real-time PCR or Western blot. ECRG4-pcDNA3.1 expressing plasmid was transfected into HepG2 cells, of which cellular proliferation, apoptosis and migration were documented. RESULTS: ECRG4 mRNA expression was reduced or absent in most primary hepatocellular carcinoma samples (95.8%, 23 out of 24 hepatocellular carcinoma samples) compared to their paired normal liver samples (P < 0.01). ECRG4 mRNA was significantly lower in HepG2 cells than QSG7701 cells (P < 0.05) along with decreased ECRG4 protein expression. HepG2 cells overexpressing ECRG4 showed decreased proliferation, increased apoptosis and reduced migration as compared with control cells (P < 0.05). CONCLUSIONS: ECRG4 expression is frequently down-regulated in hepatocellular carcinoma. Overexpression of ECRG4 inhibits the proliferation and migration but promotes apoptosis of HepG2 cells, suggesting that ECRG4 is a candidate tumor suppressor gene in hepatocellular carcinoma and therefore may serve as a novel target for precision therapy.

Multiple algorithms highlight key brain genes driven by multiple anesthetics.

Anesthesia serves as a pivotal tool in modern medicine, creating a transient state of sensory deprivation to ensure a pain-free surgical or medical intervention. While proficient in alleviating pain, anesthesia significantly modulates brain dynamics, metabolic processes, and neural signaling, thereby impairing typical cognitive functions. Furthermore, anesthesia can induce notable impacts such as memory impairment, decreased cognitive function, and diminished intelligence, emphasizing the imperative need to explore the concealed repercussions of anesthesia on individuals. In this investigation, we aggregated gene expression profiles (GSE64617, GSE141242, GSE161322, GSE175894, and GSE178995) from public repositories following second-generation sequencing analysis of various anesthetics. Through scrutinizing post-anesthesia brain tissue gene expression utilizing Gene Set Enrichment Analysis (GSEA), Robust Rank Aggregation (RRA), and Weighted Gene Co-expression Network Analysis (WGCNA), this research aims to pinpoint pivotal genes, pathways, and regulatory networks linked to anesthesia. This undertaking not only enhances comprehension of the physiological changes brought about by anesthesia but also lays the groundwork for future investigations, cultivating new insights and innovative perspectives in medical practice.

Identification of hub genes in calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is a heart valve disorder characterized primarily by calcification of the aortic valve, resulting in stiffness and dysfunction of the valve. CAVD is prevalent among aging populations and is linked to factors such as hypertension, dyslipidemia, tobacco use, and genetic predisposition, and can result in becoming a growing economic and health burden. Once aortic valve calcification occurs, it will inevitably progress to aortic stenosis. At present, there are no medications available that have demonstrated effectiveness in managing or delaying the progression of the disease. In this study, we mined four publicly available microarray datasets (GSE12644 GSE51472, GSE77287, GSE233819) associated with CAVD from the GEO database with the aim of identifying hub genes associated with the occurrence of CAVD and searching for possible biological targets for the early prevention and diagnosis of CAVD. This study provides preliminary evidence for therapeutic and preventive targets for CAVD and may provide a solid foundation for subsequent biological studies.

Multi-dimensional cell-free DNA-based liquid biopsy for sensitive early detection of gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. METHODS: We collected a prospective study cohort of 110 stage I-II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. RESULTS: Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942-0.982) in the study cohort, 0.972 (95% CI: 0.953-0.992) in the first validation cohort and 0.937 (95% CI: 0.890-0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. CONCLUSIONS: We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia.

OBJECTIVE: In B-cell acute lymphoblastic leukemia (B-ALL), current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50% of cases, underscoring the urgent need for new therapeutic regimens for this patient population. The present study aimed to determine whether HZX-02-059, a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) and tubulin, is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients. METHODS: Cell proliferation, vacuolization, apoptosis, cell cycle, and in-vivo tumor growth were evaluated. In addition, Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL. RESULTS: HZX-02-059 was found to inhibit cell proliferation, induce vacuolization, promote apoptosis, block the cell cycle, and reduce in-vivo tumor growth. Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations. CONCLUSION: Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Postural Control and Adaptation Strategy of Young Adults on Unstable Surface.

Balance control is essential for postural adjustment in physical activities. This study investigates the behavior of human postural control and the coordination and adaptation strategy of hip, knee, and ankle when standing on an unstable surface. Twenty participants were recruited. Four different conditions were investigated: a quiet bipedal stance with eyes open and eyes closed, and standing on an unstable surface with eyes open and eyes closed. Other than the joint angle, the standard body sway measures, such as sway area and sway velocity, were computed. A nonlinear time series measure, that is, sample entropy, was used to determine the regularity of the time series and body adaptability to change and perturbation. The results show that the body sway increases as the difficulty increases. This study also confirms the coordination of the hip, knee, and ankle to maintain body balance on the unstable surface by decreasing the joint angle and adopting a lower posture. Even though the individual joint has lower sample entropy value and is deemed to be rigid and less adaptive to perturbation, the postural control exhibits higher sample entropy value, particularly in the anterior-posterior direction, and has the ability to stabilize the body by manipulating the joints simultaneously. These outcomes suggest that an unstable surface not only challenges the human postural control, but also reduces the hip, knee, and ankle adaptability to perturbation, thus making it a great tool to train body balance.

Response of Spider and Epigaeic Beetle Assemblages to Overwinter Planting Regimes and Surrounding Landscape Compositions.

The rotation patterns of summer rice-winter oil seed rape and summer rice-winter fallow are the main planting regimes in the rice ecosystem in southern China. However, the impact of local rotation patterns and landscape factors on the overwintering conservation of predators in spider and epigaeic beetle assemblages remains poorly understood. Here, we investigate the diversity and density of spiders and beetles over two consecutive winters (2019/2020 and 2020/2021), focusing on the impact of two rotation patterns (rice-fallow and rice-oilseed rape) and surrounding landscape compositions on predator diversity. The main findings of our research were that spiders were more abundant and had a higher activity density in the fallow rice fields (FRs) compared to the oilseed rape fields (OSRs), whereas ground beetles exhibited the opposite pattern. Specifically, fallow rice fields supported small and ballooning spiders (e.g., dominant spider: Ummeliata insecticeps), while OSRs supported larger ground beetles (e.g., dominant beetles: Agonum chalcomus and Pterostichus liodactylus). Moreover, the composition of spider assemblages were impacted by semi-natural habitats (SNHs) during overwintering, while ground beetle assemblages were influenced by overwinter planting patterns. Overall, our results suggest that different planting regimes and preserving semi-natural habitats are a strategic way to enhance species diversity and functional diversity of ground predators. It is, therefore, recommended that to conserve and improve predator diversity during overwintering, land managers and farmers should aim to maintain diverse planting regimes and conserve local semi-natural habitats.

Performance evaluation of a CRISPR Cas9-based selective exponential amplification assay for the detection of KRAS mutations in plasma of patients with advanced pancreatic cancer.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is highly malignant, with shockingly mortality rates. KRAS oncoprotein is the main molecular target for PDAC. Liquid biopsies, such as the detection of circulating tumour DNA (ctDNA), offer a promising approach for less invasive diagnosis. In this study, we aim to evaluate the precision and utility of programmable enzyme-based selective exponential amplification (PASEA) assay for rare mutant alleles identification. METHODS: PASEA uses CRISPR-Cas9 to continuously shear wild-type alleles during recombinase polymerase amplification, while mutant alleles are exponentially amplified, ultimately reaching a level detectable by Sanger sequencing. We applied PASEA to detect KRAS mutations in plasma ctDNA. A total of 153 patients with stage IV PDAC were enrolled. We investigated the relationship between ctDNA detection rates with various clinical factors. RESULTS: Our results showed 91.43% vs 44.83% detection rate in patients of prechemotherapy and undergoing chemotherapy. KRAS ctDNA was more prevalent in patients with liver metastases and patients did not undergo surgical resection. Patients with liver metastases prior to chemotherapy showed a sensitivity of 95.24% (20/21) with PASEA. Through longitudinal monitoring, we found ctDNA may be a more accurate biomarker for monitoring chemotherapy efficacy in PDAC than CA19-9. CONCLUSIONS: Our study sheds light on the potential of ctDNA as a valuable complementary biomarker for precision targeted therapy, emphasising the importance of considering chemotherapy status, metastatic sites and surgical history when evaluating its diagnostic potential in PDAC. PASEA technology provides a reliable, cost-effective and minimally invasive method for detecting ctDNA of PDAC.

Microfluidic chip with reversible interface for noninvasive remission status monitoring and prognosis prediction of acute myeloid leukemia.

Acute myeloid leukemia (AML) requires close monitoring of remission status for timely disease management. Liquid biopsy serves as a noninvasive approach for evaluating treatment response and guiding therapeutic modifications. Herein, we designed a non-invasive Leukemic stem cell Specific Capture Chip (LSC-Chip) with reversible recognition interface for AML remission status monitoring and prognosis prediction. A stem cell marker CD34 antibody coated herringbone chip with disulfide linkers was designed to capture and release leukemic stem cells (LSCs) in peripheral blood for efficient LSC enumeration and downstream single-cell analysis. Samples from 32 AML patients and 10 healthy donors were recruited for LSC enumeration and prognosis-associated subtyping with panels of official LSC markers (CD34+/CD123+/CD38-) and (Tie2+/CD34+/CD123+/CD38-), respectively. A cutoff value of 2.5 LSCs per milliliters of peripheral blood can be used to precisely distinguish non-remission AML patients from complete remission group. Moreover, single-cell RNA-seq of LSCs was performed to check different transcriptional profiles of LSC subtypes. Overall, the LSC-Chip with reversible recognition interface enabled reliable detection of LSCs from AML patient samples for noninvasive remission status monitoring and prognosis prediction in clinical AML management.

Enhanced capacitive deionization properties of activated carbon doped with carbon nanotube-bridged molybdenum disulfide.

The shortage of freshwater supplies has restricted societal development. Capacitive deionization (CDI) is an emerging technology for desalination of seawater or brackish water, the performance of which is highly dependent on electrode materials. In this work, a molybdenum disulfide/carbon nanotube composite (CNTs-b-MoS2) with high capacitance was successfully synthesized using a hydrothermal method. The composite exhibited a specific capacitance of 112.79 F g-1. To reduce costs and determine the practicality of using CNTs-b-MoS2 for CDI, we combined activated carbon (AC) with CNTs-b-MoS2 as a CDI electrode. The research demonstrated that after doping with 5% (mass ratio) CNTs-b-MoS2, the specific capacitance and electrosorption capacity of AC were significantly improved and the maximum desalination capacity of CNTs-b-MoS2/AC reached 8.19 mg g-1. The low dosage of CNTs-b-MoS2 combined with the high specific surface area of AC avoided the shortcomings of CNTs-b-MoS2, namely low specific surface area and high cost. Moreover, the outstanding conductivity of CNTs-b-MoS2 improved the conductivity and enhanced the adsorption capacity of AC, giving CNTs-b-MoS2/AC potential as an advanced, low-cost CDI electrode material.

Stratification and therapeutic potential of ELL in cytogenetic normal acute myeloid leukemia.

Optimizing prognostic stratification of patients with cytogenetic normal acute myeloid leukemia (CN-AML), a highly heterogeneous subgroup in AML, appears to be important to improve its treatment and clinical outcome. Here, we report a potential role of ELL, a gene associated with leukemogenesis in AML, in prognostic stratification of CN-AML patients. By analyzing public available databases, we found that ELL was highly expressed in AML patients compared with healthy donors. Kaplan-Meier analysis revealed that ELL expression markedly correlated with short overall survival (OS) of CN-AML patients. In COX multivariable regression analysis, higher ELL expression was an independent prognostic factor for OS in CN-AML. Knockdown of ELL by shRNAs sensitized KG-1α cells to anti-leukemic agents such as idarubicin (IDA) and chidamide (CS055), supporting its role in therapeutic response and outcome in AML. To understand its function in CN-AML, we further analyzed the ELL-driving gene signature. ELL-related genes were particularly enriched in cell adhesion molecules, cell differentiation, pathways in cancer, sequence-specific DNA binding, and extracellular matrix (ECM)-receptor interaction. Analysis of the PPI network identified 25 hub genes, including the stem cell gene BMP4. While BMP4 expression was significantly associated with ELL in CN-AML, knockdown of ELL markedly down-regulated BMP4 expression, suggesting that ELL might function via regulating BMP4 in AML. Together, these observations suggest a novel mechanism underlying pro-leukemogenic role of ELL via BMP4 up-regulation in AML and its potential value to serve as a predictive biomarker for therapeutic response and outcome of CN-AML patients.

NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology.

C-terminal mutation of Nucleophosmin 1 (NPM1C+) was thought to be a primary driving event in acute myeloid leukemia (AML) that reprograms leukemic-associated transcription programs to transform hematopoietic stem and progenitor cells (HSPCs). However, molecular mechanisms underlying NPM1C+-driven leukemogenesis remain elusive. Here, we report that NPM1C+ activates signature HOX genes and reprograms cell cycle regulators by altering CTCF-driven topologically associated domains (TADs). Hematopoietic-specific NPM1C+ knock-in alters TAD topology leading to disrupted regulation of the cell cycle as well as aberrant chromatin accessibility and homeotic gene expression, which results in myeloid differentiation block. Restoration of NPM1 within the nucleus re-establishes differentiation programs by reorganizing TADs critical for myeloid TFs and cell cycle regulators that switch the oncogenic MIZ1/MYC regulatory axis in favor of interacting with coactivator NPM1/p300, and prevents NPM1C+-driven leukemogenesis. In sum, our data reveal that NPM1C+ reshapes CTCF-defined TAD topology to reprogram signature leukemic transcription programs required for cell cycle progression and leukemic transformation.