High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

Prognostic potential of nutritional risk screening and assessment tools in predicting survival of patients with pancreatic neoplasms: a systematic review.

BACKGROUNDS & AIMS: The nutritional evaluation of pancreatic cancer (PC) patients lacks a gold standard or scientific consensus, we aimed to summarize and systematically evaluate the prognostic value of nutritional screening and assessment tools used for PC patients. METHODS: Relevant studies were retrieved from major databases (PubMed, Embase, Web of Science, Cochrane Library) and searched from January 2010 to December 2023. We performed meta-analyses with STATA 14.0 when three or more studies used the same tool. RESULTS: This analysis included 27 articles involving 6,060 PC patients. According to a meta-analysis of these studies, poor nutritional status evaluated using five nutritional screening tools Prognostic Nutritional Index (PNI), Geriatric Nutritional Risk Index (GNRI), Controlling Nutritional Status Score (CONUT), Nutrition Risk Screening (NRS2002) and Glasgow Prognostic Score (GPS) was associated with all-cause mortality in PC patients. But Modified Glasgow Prognostic Score (mGPS) did not. Of all tools analyzed, CONUT had the maximum HR for mortality (HR = 1.978, 95%CI 1.345-2.907, P = 0.001). CONCLUSION: All-cause mortality in PC patients was predicted by poor nutritional status. CONUT may be the best nutritional assessment tool for PC patients. The clinical application value of Short Form Mini Nutritional Assessment (MNA-SF), Generated Subjective Global Assessment (SGA) and Patient-generated Subjective Global Assessment (PG-SGA) in PC patients need to be confirmed. In order to improve patients' nutritional status and promote their recovery, nutritional screening tools can be used. REGISTRATION: This systematic review was registered at the International Prospective Register of Systematic Reviews (PROSPERO) (number CRD42022376715).

Diagnosis of Benign and Malignant BI-RADS 4 Breast Masses by Contrastenhanced Ultrasound Combined with Shear Wave Elastography.

BACKGROUND: Breast cancer, one of the most prevalent malignant tumors in females, usually occurs in the breast epithelial tissues. OBJECTIVE: The study aimed to explore the diagnostic value of contrast-enhanced ultrasound (CEUS) combined with shear wave elastography (SWE) in the diagnosis of benign and malignant breast masses in BI-RADS (Breast Imaging Reporting and Data System) 4. METHODS: Examination outcomes and clinical information of 83 patients with BI-RADS 4 breast masses were analyzed retrospectively. These included patients who received CEUS, SWE, and pathological examinations. The difference of CEUS in determining the classification of BI-RADS 4 breast masses was evaluated using histopathological outcomes of breast masses as a reference standard. The diagnostic value of CEUS, SWE, and CEUS combined with SWE in the diagnosis of benign and malignant breast masses in BI-RADS 4 was also explored. RESULTS: Pathological biopsy results revealed 63 malignant masses and 20 benign masses among 83 BI-RADS 4 breast masses, with a 75.9% incidence of malignant masses. After the diagnosis of BI-RADS 4 breast masses with CEUS, SWE, and CEUS+SWE, the incidence of malignancy was 56.6%, 78.3%, and 73.5%, respectively. CEUS+SWE showed higher sensitivity (93.7% vs. 81% and 68.3%), specificity (90% vs. 30% and 80%), positive predictive value (96.7% vs. 78.5% and 91.5%), negative predictive value (81.8% vs. 33.3% and 44.4%), and diagnostic coincidence rate (92.8% vs. 68.7% and 71.1%) than SWE and CEUS alone in diagnosing pathological type of breast masses. Moreover, CEUS combined with SWE exhibited a larger area under the receiver operating characteristic (ROC) curve (0.918) than SWE (0.741, p = 0.028) and CEUS (0.555, p < 0.001) alone in the diagnosis of BI-RADS 4 breast masses. CONCLUSION: Overall, the diagnostic value of CEUS+SWE for the pathological type of BI-RADS is preferred over CEUS and SWE alone. CEUS+SWE showed higher values than CEUS and SWE alone in diagnosing BI-RADS 4 breast masses. Specifically, CEUS+SWE can correctly identify benign and malignant masses, reduce unnecessary trauma, and avoid misdiagnosis. In summary, CEUS combined with SWE can serve as an effective diagnostic method and avoid delaying the best treatment opportunity for some malignant lesions.

Parasitic capacitance modeling and measurements of conductive yarns for e-textile devices.

Conductive yarns have emerged as a viable alternative to metallic wires in e-Textile devices, such as antennas, inductors, interconnects, and more, which are integral components of smart clothing applications. But the parasitic capacitance induced by their micro-structure has not been fully understood. This capacitance greatly affects device performance in high-frequency applications. We propose a lump-sum and turn-to-turn model of an air-core helical inductor constructed from conductive yarns, and systematically analyze and quantify the parasitic elements of conductive yarns. Using three commercial conductive yarns as examples, we compare the frequency response of copper-based and yarn-based inductors with identical structures to extract the parasitic capacitance. Our measurements show that the unit-length parasitic capacitance of commercial conductive yarns ranges from 1 fF/cm to 3 fF/cm, depending on the yarn's microstructure. These measurements offer significant quantitative estimation of conductive yarn parasitic elements and provide valuable design and characterization guidelines for e-Textile devices.

High Expression of CD300A Predicts Poor Survival in Acute Myeloid Leukemia.

INTRODUCTION: Recent studies have suggested that CD300A was an oncogene in acute myeloid leukemia (AML) development. However, the clinical relevance and biological insight into CD300A expression in AML are still not well understood. The present study aimed to examine the expression characteristics of CD300A in AML and confirmed its clinical significance for AML. METHODS: Quantification of the CD300A transcript was performed in 119 AML patients by real-time quantitative PCR in bone marrow blasts. The predictive significance of CD300A expression on the clinical outcomes of AML was assessed using overall survival (OS) and relapse-free survival (RFS). The published Cancer Genome Atlas (TCGA) data were used as an external validation for survival analysis and pathway analyses. RESULTS: In comparison with monocytes from healthy peripheral blood cells, the expression levels of CD300A in AML cells were higher. Patients in the intermediate and adverse risk categories by WHO criteria (2018) had higher CD300A expression levels than those in the favorable risk category (p < 0.001). AML patients with high expression of CD300A had a higher early death rate (p = 0.029), lower complete remission rate (p = 0.042), higher death rate (p < 0.001) and relapse rate (p = 0.002), and shorter OS (p < 0.0001) and RFS (p < 0.0001). Through multivariable analysis, high CD300A expression in AML was also an independent poor prognostic factor. The CAMP and CGMP-PKG signaling pathways may be stimulated by increased CD300A expression levels, which may be important for the development of AML. CONCLUSIONS: The expression levels of CD300A were associated with risk stratification and the clinical relevance of AML. High CD300A expression may act as an independent adverse prognostic factor for OS and RFS in AML.

Construction of ß-Amino Sulfones from Sodium Metabisulfite via a Radical 1,4-Amino Migration.

A three-component reaction of alkenyl-tethered oxime ethers, sodium metabisulfite, and aryldiazonium tetrafluoroborates under mild conditions is developed. This reaction proceeds at room temperature without any oxidants or additives, affording ß-amino sulfones with good functional group tolerance through aminosulfonylation of unactivated alkene. Mechanistic studies show that this transformation undergoes a radical process, including radical trapping with sulfur dioxide and radical 1,4-amino migration.

The posterior middle temporal gyrus serves as a hub in syntactic comprehension: A model on the syntactic neural network.

Neuroimaging studies have revealed a distributed neural network involving multiple fronto-temporal regions that are active during syntactic processing. Here, we investigated how these regions work collaboratively to support syntactic comprehension by examining the behavioral relevance of the global functional integration of the syntax network (SN). We found that individuals with a stronger resting-state within-network integration in the left posterior middle temporal gyrus (lpMTG) were better at syntactic comprehension. Furthermore, the pair-wise functional connectivity between the lpMTG and the Broca's area, the middle frontal gyrus, and the angular and supramarginal gyri was positively correlated with participants' syntactic processing ability. In short, our study reveals the behavioral significance of intrinsic functional integration of the SN in syntactic comprehension, and provides empirical evidence for the hub-like role of the lpMTG. We proposed a neural model for syntactic comprehension highlighting the hub of the SN and its interactions with other regions in the network.

An All-Fabric Tactile-Sensing Keypad with Uni-Modal and Ultrafast Response/Recovery Time for Smart Clothing Applications.

Keypads constructed from fabric materials are the ideal input devices for smart clothing applications. However, multi-modal reaction problems have to be addressed before they can be of practical use on apparels, i.e., the fabric-based keypads need to distinguish between the legitimate actions by the fingertips and the illegitimate deformations and stresses caused by human movements. In this paper, we propose to use the humidity sensor functionalized from graphene oxide (GO)-coated polyester fibers to construct the e-textile keypads. As the moisture level in the proximity of human fingertips is much higher (over 70%) than other parts of the human body, humidity sensing has many advantages over other tactility mechanisms. Experiments have demonstrated that the GO-functionalized fabric keypad has a stable uni-modal tactility only to fingertip touches, and it is not sensitive to deformation, pressure, temperature variation, and other ambient interferences. With biasing and sensing circuits, the keypad exhibits a quick response and recovery time (around 0.1 s), comparable to mechanical keyboards. To demonstrate its application on smart clothing, the keypad was sewn on a sweater and embroidered conductive yarns were used to control an MP3 player in the pocket.

Attention impedes neural representation of interpolated orientation during perceptual completion.

One of the most remarkable functional feats accomplished by visual system is the interpolation of missing retinal inputs based on surrounding information, a process known as perceptual completion. Perceptual completion enables the active construction of coherent, vivid percepts from spatially discontinuous visual information that is prevalent in real-life visual scenes. Despite mounting evidence linking sensory activity enhancement and perceptual completion, surprisingly little is known about whether and how attention, a fundamental modulator of sensory activities, affects perceptual completion. Using EEG-based time-resolved inverted encoding model (IEM), we reconstructed the moment-to-moment representation of the illusory grating that resulted from spatially interpolating the orientation of surrounding inducers. We found that, despite manipulation of observers' attentional focus, the illusory grating representation unfolded in time in a similar manner. Critically, attention to the surrounding inducers simultaneously attenuated the illusory grating representation and delayed its temporal development. Our findings disclosed, for the first time, the suppressive role of selective attention in perceptual completion and were suggestive of a fast, automatic neural machinery that implements the interpolation of missing visual information.

Anti-PD-1 treatment-induced immediate central diabetes insipidus: a case report.

Modulating PD-1 expression can constrain tumor growth. Hodgkin's lymphoma patients commonly express PD-L1 on tumor cells. We report the case of a 60-year-old male patient with relapsed classical Hodgkin's lymphoma who suffered from immediate-onset chill, hyperthermia and polyuria following initial treatment with sintilimab, an anti-PD-1 monoclonal antibody. The results revealed central diabetes insipidus (cDI). After 3 months of treatment with glucocorticoids and desmopressin acetate, his symptoms and the results were consistent with the resolution of cDI and the treatment course was discontinued. Diabetes insipidus is a rare complication of immunotherapeutic treatment, and this is the first case report to our knowledge to have described immediate-onset cDI caused by anti-PD-1 treatment.

Lay abstract For relapsed classical Hodgkin's lymphoma, anti-PD-1 monoclonal antibodies have been related to potent safety profiles and efficacy. Reported here is a case of a 60-year-old man diagnosed as having relapsed classical Hodgkin's lymphoma. He achieved a durable response over 4 months with four rounds of traditional chemotherapy, and then the disease relapsed. Sintilimab, an anti-PD-1 monoclonal antibody, was executed for salvage therapy. In spite of the patient-acquired durable response, central diabetes insipidus was detected after the first application of sintilimab. According to our knowledge this is the first case to report immediate-onset central diabetes insipidus caused by the treatment of anti-PD-1. In the present study, we discussed and analyzed the types and clinical causes of diabetes insipidus for this patient.

Chirality parameter sensing based on surface plasmon resonance D-type photonic crystal fiber sensors.

We report a method to sense a surrounding chiral drug based on D-type single-mode photonic crystal fiber (PCF) sensors in this paper. The electromagnetic theory of surface plasmon resonance on metal-chiral drug structure is derived. The wave equation containing constitutive relations of a chiral drug is given and integrated into the finite element method to compute the effective refractive index, confinement loss, and plasmon resonance wavelength for a D-type PCF sensor immersed in the chiral drug. The effects of the chirality parameter on resonance behaviors are displayed. The wavelength sensitivities of the chirality parameter for the sensor changing with different kinds of metal film layers, side-polished depth, and thickness of metal film layer are calculated. The wavelength sensitivity can reach a maximum of 17,580 nm/chirality as the refractive index and chirality parameter of the drug are 1.36 and 0.08, respectively. Furthermore, simultaneous dual-parameter detection of the chirality parameter and refractive index is realized by using two different D-type PCF sensors with gold and silver metal film layers, respectively. This study may provide sufficient guidelines to the field of biochemical sensing.

Visual association learning induces global network reorganization.

It has been proposed that visual learning is accomplished not only by neural plasticity in the visual cortex, but also by complex interactions between bottom-up and top-down processes that may induce global network reorganization. Here, we applied a multivariate analysis to functional connectivity (FC) patterns across the brain to investigate how visual association learning was achieved through large-scale network reorganization. Participants were trained to associate a set of artificial line-drawing objects with English letters. After three consecutive days of training, participants underwent a functional magnetic resonance imaging scan in which they were presented with the trained stimuli, untrained stimuli, and English words. By calculating pairwise FC between 189 nodes of 10 well-established networks across the brain, we found that the visual association learning induced changes in the global FC pattern when viewing the trained stimuli, rendering it more similar to the FC pattern when viewing English words. Critically, the learning-induced global FC pattern differences were mainly driven by the FC related to the high-level networks involved in attention and cognitive control, suggesting the modification of top-down processes during learning. In sum, our study provides one of the first evidence revealing global network reorganization induced by visual learning and sheds new light on the network mechanisms of top-down influences in learning.

Motor Learning Improves the Stability of Large-Scale Brain Connectivity Pattern.

Repeated practice is fundamental to the acquisition of skills, which is typically accompanied by increasing reliability of neural representations that manifested as more stable activation patterns for the trained stimuli. However, large-scale neural pattern induced by learning has been rarely studied. Here, we investigated whether global connectivity patterns became more reliable as a result of motor learning using a novel analysis of the multivariate pattern of functional connectivity (MVPC). Human participants were trained with a finger-tapping motor task for five consecutive days and went through Functional magnetic resonance imaging (fMRI) scanning before and after training. We found that motor learning increased the whole-brain MVPC stability of the primary motor cortex (M1) when participants performed the trained sequence, while no similar effects were observed for the untrained sequence. Moreover, the increase of MVPC stability correlated with participants' improvement in behavioral performance. These findings suggested that the acquisition of motor skills was supported by the increased connectivity pattern stability between the M1 and the rest of the brain. In summary, our study not only suggests global neural pattern stabilization as a neural signature for effective learning but also advocates applying the MVPC analysis to reveal mechanisms of distributed network reorganization supporting various types of learning.

miR-550-1 functions as a tumor suppressor in acute myeloid leukemia via the hippo signaling pathway.

MicroRNAs (miRNAs) and N6-methyladenosine (m6A) are known to serve as key regulators of acute myeloid leukemia (AML). Our previous microarray analysis indicated miR-550-1 was significantly downregulated in AML. The specific biological roles of miR-550-1 and its indirect interactions and regulation of m6A in AML, however, remain poorly understood. At the present study, we found that miR-550-1 was significantly down-regulated in primary AML samples from human patients, likely owing to hypermethylation of the associated CpG islands. When miR-550-1 expression was induced, it impaired AML cell proliferation both in vitro and in vivo, thus suppressing tumor development. When ectopically expressed, miR-550-1 drove the G0/1 cell cycle phase arrest, differentiation, and apoptotic death of affected cells. We confirmed mechanistically that WW-domain containing transcription regulator-1 (WWTR1) gene was a downstream target of miR-550-1. Moreover, we also identified Wilms tumor 1-associated protein (WTAP), a vital component of the m6A methyltransferase complex, as a target of miR-550-1. These data indicated that miR-550-1 might mediate a decrease in m6A levels via targeting WTAP, which led to a further reduction in WWTR1 stability. Using gain- and loss-of-function approaches, we were able to determine that miR-550-1 disrupted the proliferation and tumorigenesis of AML cells at least in part via the direct targeting of WWTR1. Taken together, our results provide direct evidence that miR-550-1 acts as a tumor suppressor in the context of AML pathogenesis, suggesting that efforts to bolster miR-550-1 expression in AML patients may thus be a viable clinical strategy to improve patient outcomes.

Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro.

Background: Apigenin, a flavonoid phytochemical extracted from fruits and vegetables, has shown anti-neoplastic effects in a variety of malignant tumors. DLBCL is the most common type of aggressive lymphoma in adults with a poor prognosis. Small-molecule inhibitors like BTK inhibitors have demonstrated extended period of disease control. Whereas the effects of the synergetic inhibition of the two have not been elucidated. Methods: We assessed the efficacy of Apigenin alone or combined with Abivertinib to inhibit DLBCL progression. Cell viability was examined using the cell proliferation cell proliferation assay (MTS). Apoptotic cells and cell cycle evaluation were detected by Annexin V-FITC and DNA staining solution respectively. Western blot was used to explore the potential mechanism, and the in vivo effects of the two drugs were performed by a DLBCL xenograft BALB/c nude mice model. Results: Our results demonstrated that Apigenin can inhibit the proliferation and clone forming of DLBCL cells. Apigenin also induces apoptosis by down-regulating BCL-XL and activating Caspase family. In addition, Apigenin down-regulates cell cycle proteins including CDK2/CDK4/CDK6/CDC2/p-RB to increase G2/M phase arrest. Mechanically, our data demonstrate that Apigenin leads to a significant reduction of the expression of pro-proliferative pathway PI3K/mTOR to inhibit DLBCL cells survival. Moreover, our in vitro and in vivo results show that Apigenin can synergize with Abivertinib, a novel BTK inhibitor, in treating DLBCL visa synergistically inducing apoptosis and inhibiting the p-GS3K-ß and its downstream targets. Conclusions: Collectively, our study suggests that Apigenin exerts improving anti-lymphoma effect of BTK inhibitors and provides hope to targeted therapy of those develop resistance.

The relationship between consumption of nitrite or nitrate and risk of non-Hodgkin lymphoma.

Epidemiologic studies of the relationship between nitrite or nitrate consumption and risk of non-Hodgkin lymphoma (NHL) remain controversial. The current meta-analysis aimed to reexamine the evidence and quantitatively evaluate that relationship. Manuscripts were retrieved from the Web of Science, Chinese National Knowledge Infrastructure and PubMed databases up to May 2019. From the studies included in the review, results were combined and presented as odds ratios (OR). To conduct a dose-response (DR) analysis, studies presenting risk estimates over a series of categories of exposure were selected. Our data indicate that the consumption of nitrite was linked to a significantly increased hazard of NHL (OR: 1.37; 95% CI: 1.14-1.65), rather than nitrate (OR: 1.02; 95% CI: 0.94-1.10). According to Egger's and Begg's tests (P > 0.05), there was no evidence of significant publication bias. Moreover, our DR analysis indicated that the risk of NHL grew by 26% for each additional microgram of nitrite consumed in the diet per day (OR: 1.26; 95% CI: 1.09-1.42). Through subset analysis of the nitrite studies, data from the high-quality studies indicated that consumption was positively associated with carcinogenicity, leading to NHL (OR: 1.44; 95% CI: 1.17-1.77) and positively correlated with the development of diffuse large B-cell lymphoma (OR: 1.55; 95% CI: 1.07-2.26), but not other NHL subtypes. In addition, the data suggested that females (OR: 1.50; 95% CI: 1.15-1.95) and high levels of nitrite intake (OR: 1.64; 95% CI: 1.28-2.09) had a higher risk of NHL. Our meta-analysis supports the hypothesis that nitrite intake, but not that of nitrate, raises the risk of developing NHL. In the future, better designed prospective research studies should be conducted to confirm our findings, clarify potential biological mechanisms and instruct clinicians about NHL prophylaxis.

Resting-State Functional Connectivity of the Punishment Network Associated With Conformity.

Fear of punishment prompts individuals to conform. However, why some people are more inclined than others to conform despite being unaware of any obvious punishment remains unclear, which means the dispositional determinants of individual differences in conformity propensity are poorly understood. Here, we explored whether such individual differences might be explained by individuals' stable neural markers to potential punishment. To do this, we first defined the punishment network (PN) by combining all potential brain regions involved in punishment processing. We subsequently used a voxel-based global brain connectivity (GBC) method based on resting-state functional connectivity (FC) to characterize the hubs in the PN, which reflected an ongoing readiness state (i.e., sensitivity) for potential punishment. Then, we used the within-network connectivity (WNC) of each voxel in the PN of 264 participants to explain their tendency to conform by using a conformity scale. We found that a stronger WNC in the right thalamus, left insula, postcentral gyrus, and dACC was associated with a stronger tendency to conform. Furthermore, the FC among the four hubs seemed to form a three-phase ascending pathway, contributing to conformity propensity at every phase. Thus, our results suggest that task-independent spontaneous connectivity in the PN could predispose individuals to conform.

Sex-Specific Functional Connectivity in the Reward Network Related to Distinct Gender Roles.

Gender roles are anti-dichotomous and malleable social constructs that should theoretically be constructed independently from biological sex. However, it is unclear whether and how the factor of sex is related to neural mechanisms involved in social constructions of gender roles. Thus, the present study aimed to investigate sex specificity in gender role constructions and the corresponding underlying neural mechanisms. We measured gender role orientation using the Bem Sex-Role Inventory, used a voxel-based global brain connectivity method based on resting-state functional magnetic resonance imaging to characterize the within-network connectivity in the brain reward network, and analyzed how the integration of the reward network is related to gender role scores between sex groups. An omnibus analysis of voxel-wise global brain connectivity values within a two-level linear mixed model revealed that in female participants, femininity scores were positively associated with integration in the posterior orbitofrontal cortex and subcallosal cortex, whereas masculinity scores were positively associated with integration in the frontal pole. By contrast, in male participants, masculinity was negatively correlated with integration in the nucleus accumbens and subcallosal cortex. For the first time, the present study revealed the sex-specific neural mechanisms underlying distinct gender roles, which elucidates the process of gender construction from the perspective of the interaction between reward sensitivity and social reinforcement.

Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC.

Homoharringtonine, a plant alkaloid, has been reported to suppress protein synthesis and has been approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia. Here we show that in acute myeloid leukemia (AML), homoharringtonine potently inhibits cell growth/viability and induces cell cycle arrest and apoptosis, significantly inhibits disease progression in vivo, and substantially prolongs survival of mice bearing murine or human AML. Strikingly, homoharringtonine treatment dramatically decreases global DNA 5-hydroxymethylcytosine abundance through targeting the SP1/TET1 axis, and TET1 depletion mimics homoharringtonine's therapeutic effects in AML. Our further 5hmC-seq and RNA-seq analyses, followed by a series of validation and functional studies, suggest that FLT3 is a critical down-stream target of homoharringtonine/SP1/TET1/5hmC signaling, and suppression of FLT3 and its downstream targets (e.g. MYC) contributes to the high sensitivity of FLT3-mutated AML cells to homoharringtonine. Collectively, our studies uncover a previously unappreciated DNA epigenome-related mechanism underlying the potent antileukemic effect of homoharringtonine, which involves suppression of the SP1/TET1/5hmC/FLT3/MYC signaling pathways in AML. Our work also highlights the particular promise of clinical application of homoharringtonine to treat human AML with FLT3 mutations, which accounts for more than 30% of total cases of AML.

Correction: The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia.

[This corrects the article DOI: 10.18632/oncotarget.14463.].