Preparation of liquid silicon-based carbon dots and application for luminescent solar concentrators.

Liquid silicon-based carbon dots (CDs) with a photoluminescence quantum yield (PLQY) of 50% were prepared using N-[3-(trimethoxysilyl)propyl]ethylenediamine (DAMO), citric acid, and n-butylamine as raw materials. Firstly, the optimized characters have been determined, namely, the optimal DAMO, citric acid, and n-butylamine addition amounts of 1 mL, 0.9 g, and 1 mL, a reaction time of 3 h, and a reaction temperature of 160°C. Further research has confirmed that the increase in fluorescence intensity of CDs is mainly due to the introduction of DAMO, in which the two amino groups in DAMO play a major role. In addition, the Si-O-Si group generated by the hydrolysis of siloxane groups is connected to the surface of the CDs and forms a core-shell structure, which modifies the defects on the surface and enhances the fluorescence intensity of the CDs. Finally, luminescent solar concentrators (LSCs) based on liquid silicon-based CDs were assembled by spin coating. The obtained device has a transparency of up to 80% and an optical efficiency of 2.4%.

Perfusion index to predict post spinal hypotension in lower segment caesarean section.

Background and Aims: It is important to predict and prevent post-spinal hypotension in lower segment cesarean section (LSCS). Peripheral vascular tone can be monitored as a perfusion index (PI) from a pulse oximeter. We aimed to study baseline PI as a predictor of post-spinal hypotension in LSCS. Material and Methods: Prospective observational study conducted in a tertiary care teaching public hospital on patients posted for elective LSCS under spinal anesthesia. Baseline PI and hypotension were compared. A receiver operating characteristic (ROC) curve was plotted and data were analyzed using SPSS version 20. Results: Among 90 females, 43 (47.8%) had a PI ≤3.5 and 47 (52.2%) had a PI >3.5. In the PI >3.5 group, 46 (97.9%) females had hypotension and required a high volume of IV fluids, and 29 (61.7%) required vasopressors, and the association with PI was statistically significant with Pearson's Chi-square values of 32.26 and 32.36, respectively (P = 0.001). In the ROC, the area under the curve (AUC) was 0.917, proving baseline PI >2.9 as an excellent classifier (P < 0.0001,95% confidence interval [CI] 0.840-0.965) and can predict hypotension with a sensitivity of 83.08% and specificity of 96.00%. Conclusion: Baseline PI >3.5 was associated with significant post-spinal hypotension and vasopressor administration in LSCS. We established baseline PI >2.9 can predict post-spinal hypotension with high sensitivity and specificity. PI is simple, quick, and non-invasive and can be used as a predictor for post-spinal hypotension in parturients undergoing LSCS so that prophylactic measures can be considered in at-risk patients for better maternal and fetal outcomes.

Senescence Promotes the Recovery of Stemness among Cancer Cells via Reprograming.

Both the senescence of cancer cells and the maintenance of cancer stem cells seem to be mutually exclusive because senescence is considered a physiological mechanism that effectively suppresses tumor growth. Recent studies have revealed common signaling pathways between cellular senescence and the maintenance of stemness in cancer cells, thus challenging the conventional understanding of this process. Although the links between these processes have not yet been fully elucidated, emerging evidence indicates that senescent cancer cells can undergo reprograming to recover stemness. Herein, we provide a comprehensive overview of the close correlation between senescence and stemness reprograming in cancer cells, with a particular focus on the mechanisms by which senescent cancer cells recover their stemness in various tumor systems.

Anesthetic Challenges Associated With Posterior Reversible Encephalopathy Syndrome in a Pregnant Woman Scheduled for a Caesarean Section.

Recently, there has been a rise in reports of posterior reversible encephalopathy syndrome (PRES), which is an uncommon neurologic illness. The precise cause of PRES syndrome is yet unknown, but there are certain illnesses that have been associated with it. Furthermore, because of advances in imaging methods and growing awareness, the connection between PRES and pre-eclampsia/eclampsia is becoming increasingly recognised. Pre-eclampsia/eclampsia by itself poses distinct perioperative difficulties; in addition, PRES makes anesthesia administration more difficult. Regretfully, there is a lack of knowledge regarding the anesthetic treatment provided to the extremely sick and medically complex patients, and it is uncertain whether the chosen anesthetic might exacerbate neurologic problems. Here, we discuss the implications for the anesthetic management of PRES presentations.

The diagnostic accuracy of preoperative perfusion index as a predictor of postspinal anesthesia hypotension in parturients undergoing cesarean delivery: A prospective non-blinded observational study.

Background and Objectives: Spinal anesthesia is the technique of choice for elective cesarean section with a prominent side effect of postspinal anesthesia hypotension (PSH). This needs an early prediction to avoid feto-maternal complication. This study aimed to assess the diagnostic accuracy of perfusion index (PI) and inferior vena cava collapsibility index (IVCCI) in the prediction of PSH. Material and Methods: Thirty parturients of American Society of Anesthesiologists Physical Status (ASA-PS) 1 and two undergoing cesarean delivery participated in the study. IVCCI, PI, baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and heart rate (HR) were noted in the preoperative period. The fall of MBP by 20% from baseline or below 65 mm Hg was considered PSH. After spinal anesthesia, SBP, DBP, MBP, and HR were noted again for diagnosing PSH. Results: It did not show any statistical difference when comparing the PI between the PSH and non-PSH groups in both the PSH definition groups. IVCCI was significantly higher when PSH was considered MBP <65 mm Hg (P = 0.01). However, IVCCI was found to be statistically insignificant if PSH was considered a 20% reduction in baseline MBP. The correlation matrix between IVCCI and PI showed Pearson's r-value of 0.525, indicating a substantial relationship between the two (P = 0.003). Multivariate logistic regression analysis had shown that neither IVCCI nor PI was a good predictor of PSH in parturients for both definition groups for PSH. Conclusion: Although there is a modest correlation between PI and IVCCI, both cannot be used to predict postspinal hypotension in parturients undergoing elective lower-segment cesarean section (LSCS).

Intracranial hypotension with subdural hematoma after spinal anesthesia in obstetric patient: A rare but fatal complication.

Intracranial bleed in the form of subdural hematoma (SDH) with intracranial hypotension after spinal anesthesia for cesarean section is a rare condition with an incidence of around 1 in 5,00,000 obstetric populations. As its presentation is similar to post-dural puncture headache (PDPH), it can be misdiagnosed sometimes. Persistent headache for more than 5 days, vomiting, blurring of vision, and convulsion can guide the diagnosis of intracranial bleed. Magnetic resonance imaging (MRI) helps to diagnose the location, size, and other abnormalities of bleed in such patients. The management ranges from conservative to surgical management in the form of craniotomy. Here, we present a case of a 19-year-old woman, who operated on for cesarean section under spinal anesthesia presented with SDH and intracranial hypotension on postoperative day (POD) 6. She was managed conservatively with plenty of intravenous (IV) fluids, bed rest, low head position, analgesics, and antiepileptics. A repeat computed tomography (CT) scan was performed after 14 days, which showed resolved SDH, and the patient was discharged.

PHF6 loss reduces leukemia stem cell activity in an acute myeloid leukemia mouse model.

Acute myeloid leukemia (AML) is a malignant hematologic disease caused by gene mutations and genomic rearrangements in hematologic progenitors. The PHF6 (PHD finger protein 6) gene is highly conserved and located on the X chromosome in humans and mice. We found that PHF6 was highly expressed in AML cells with MLL rearrangement and was related to the shortened survival time of AML patients. In our study, we knocked out the Phf6 gene at different disease stages in the AML mice model. Moreover, we knocked down PHF6 by shRNA in two AML cell lines and examined the cell growth, apoptosis, and cell cycle. We found that PHF6 deletion significantly inhibited the proliferation of leukemic cells and prolonged the survival time of AML mice. Interestingly, the deletion of PHF6 at a later stage of the disease displayed a better anti-leukemia effect. The expressions of genes related to cell differentiation were increased, while genes that inhibit cell differentiation were decreased with PHF6 knockout. It is very important to analyze the maintenance role of PHF6 in AML, which is different from its tumor-suppressing function in T-cell acute lymphoblastic leukemia (T-ALL). Our study showed that inhibiting PHF6 expression may be a potential therapeutic strategy targeting AML patients.

Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib: Implications for Therapy Resistance.

Leukemic stem cells (LSCs) possess similar characteristics to normal hematopoietic stem cells, including self-renewal capacity, quiescence, ability to initiate leukemia, and drug resistance. These cells play a significant role in leukemia relapse, persisting even after apparent remission. LSCs were first described in 1994 by Lapidot et al. Although they have been extensively studied in acute leukemia, more LSC research is still needed in chronic lymphocytic leukemia (CLL) to understand if reduced apoptosis in mature cells should still be considered as the major cause of this disease. Here, we provide new evidence suggesting the existence of stem-like cell populations in CLL, which may help to understand the disease as well as to develop effective treatments. In this study, we identified a potential leukemic stem cell subpopulation using the tetraploid CLL cell line I83. This subpopulation is characterized by diploid cells that were capable of generating the I83 tetraploid population. Furthermore, we adapted a novel flow cytometry analysis protocol to detect CLL subpopulations with stem cell properties in peripheral blood samples and primary cultures from CLL patients. These cells were identified by their co-expression of CD19 and CD5, characteristic markers of CLL cells. As previously described, increased alkaline phosphatase (ALP) activity is indicative of stemness and pluripotency. Moreover, we used this method to investigate the potential synergistic effect of curcumin in combination with fludarabine and ibrutinib to deplete this subpopulation. Our results confirmed the effectiveness of this ALP-based analysis protocol in detecting and monitoring leukemic stem-like cells in CLL. This analysis also identified limitations in eradicating these populations using in vitro testing. Furthermore, our findings demonstrated that curcumin significantly enhanced the effects of fludarabine and ibrutinib on the leukemic fraction, exhibiting synergistic effects (combination drug index, CDI 0.97 and 0.37, respectively). Our results lend support to the existence of potential stem-like populations in CLL cell lines, and to the idea that curcumin could serve as an effective adjuvant in therapies aimed at eliminating these populations and improving treatment efficacy.

MEIS inhibitors reduce the viability of primary leukemia cells and Stem cells by inducing apoptosis.

Leukemia stem cells (LSCs) exhibit self-renewal, resistance to standard treatments, and involvement in leukemia relapse. Higher Myeloid Ecotropic Integration Site-1 (MEIS1) expression in leukemic blast samples has been linked to resistance to conventional treatment. We studied the MEIS1 and associated factors in relapsed LSCs and assessed the effect of recently developed MEIS inhibitors (MEISi). Meis1 gene expression was found to be higher in patients with leukemia and relapsed samples. The majority of CD123+ and CD34+ LSCs demonstrated higher MEIS1/2/3 content. Depending on the patient chemotherapy regimen, Meis1 expression increased in relapsed samples. Although there are increased Meis2, Meis3, Hoxa9, Pbx1, or CD34 expressions in the relapsed patients, they are not correlated with Meis1 content in every patient or regimen. MEISi has reduced MEIS1 transcriptional activity and LSC cell survival by apoptosis. Pharmacological targeting with MEISi in LSCs could have a potential effect in limiting leukemia relapse and chemotherapeutic resistance.

Comparison of Clinical and Radiological Findings for the Prediction of Scar Integrity in Women With Previous Lower Segment Cesarean Sections.

INTRODUCTION: We aimed to compare the clinical and radiological findings to predict scar integrity in term antenatal mothers with a previous lower segment cesarean section (LSCS). METHODOLOGY: This prospective study was conducted in the obstetrics and gynecology department of LN Medical College, Bhopal, India, from August 2020 to August 2021. We included all pregnant women with term gestation (37+0 to 42+0 weeks) who were admitted either for elective repeat LSCS or for emergency LSCS and had a history of a previous LSCS. A detailed history and clinical examinations were performed. We noted the presence of scar tenderness and conducted transabdominal ultrasound (USG) to assess the integrity of the uterine scar in all women. During surgery, the surgeon identified the lower uterine segment scar and graded it as normal, thinned-out, dehiscent, or ruptured. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for both clinical findings (scar tenderness) and ultrasound findings as predictors of scar integrity. RESULTS: A total of 60 pregnant women were included in the study. During a repeat cesarean section, we found a thinned-out scar in 26 women out of 60 (43.3%). Out of 60 women, 13 had scar tenderness, and among these 13 women, 12 had thinned-out scars intraoperatively. Forty-seven women had no scar tenderness; 14 had thinned-out scars intraoperatively. The sensitivity of scar tenderness as a predictor of a thinned-out scar was 46.2%, specificity was 97.1%, PPV was 92.3%, and NPV was 70.2%. Whereas the sensitivity of ultrasound scar thickness as a predictor of a thinned-out scar was only 19.2%, with a specificity of 94.1%, a PPV of 71.4%, and an NPV of 60.4%. Thus, we documented a significant correlation between intraoperative and clinical findings (κ = 0.46; p<0.05), but no agreement could be found between ultrasound and intraoperative findings (p>0.05). CONCLUSIONS: Clinically evident scar tenderness continues to be a useful parameter to predict intraoperative scar status.

Therapeutic targeting of leukemia stem cells in acute myeloid leukemia.

One of the distinguishing properties of hematopoietic stem cells is their ability to self-renew. Since self-renewal is important for the continuous replenishment of the hematopoietic stem cell pool, this property is often hijacked in blood cancers. Acute myeloid leukemia (AML) is believed to be arranged in a hierarchy, with self-renewing leukemia stem cells (LSCs) giving rise to the bulk tumor. Some of the earliest characterizations of LSCs were made in seminal studies that assessed the ability of prospectively isolated candidate AML stem cells to repopulate the entire heterogeneity of the tumor in mice. Further studies indicated that LSCs may be responsible for chemotherapy resistance and therefore act as a reservoir for secondary disease and leukemia relapse. In recent years, a number of studies have helped illuminate the complexity of clonality in bone marrow pathologies, including leukemias. Many features distinguishing LSCs from normal hematopoietic stem cells have been identified, and these studies have opened up diverse avenues for targeting LSCs, with an impact on the clinical management of AML patients. This review will discuss the role of self-renewal in AML and its implications, distinguishing characteristics between normal and leukemia stem cells, and opportunities for therapeutic targeting of AML LSCs.

The Therapeutic Potential of a Strategy to Prevent Acute Myeloid Leukemia Stem Cell Reprogramming in Older Patients.

Acute myeloid leukemia (AML) is the most common and incurable leukemia subtype. Despite extensive research into the disease's intricate molecular mechanisms, effective treatments or expanded diagnostic or prognostic markers for AML have not yet been identified. The morphological, immunophenotypic, cytogenetic, biomolecular, and clinical characteristics of AML patients are extensive and complex. Leukemia stem cells (LSCs) consist of hematopoietic stem cells (HSCs) and cancer cells transformed by a complex, finely-tuned interaction that causes the complexity of AML. Microenvironmental regulation of LSCs dormancy and the diagnostic and therapeutic implications for identifying and targeting LSCs due to their significance in the pathogenesis of AML are discussed in this review. It is essential to perceive the relationship between the niche for LSCs and HSCs, which together cause the progression of AML. Notably, methylation is a well-known epigenetic change that is significant in AML, and our data also reveal that microRNAs are a unique factor for LSCs. Multiple-targeted approaches to reduce the risk of epigenetic factors, such as the administration of natural compounds for the elimination of local LSCs, may prevent potentially fatal relapses. Furthermore, the survival analysis of overlapping genes revealed that specific targets had significant effects on the survival and prognosis of patients. We predict that the multiple-targeted effects of herbal products on epigenetic modification are governed by different mechanisms in AML and could prevent potentially fatal relapses. Thus, these strategies can facilitate the incorporation of herbal medicine and natural compounds into the advanced drug discovery and development processes achievable with Network Pharmacology research.

Acute Myeloid Leukemia Stem Cells in Minimal/Measurable Residual Disease Detection.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by an abundance of incompletely matured or immature clonally derived hematopoietic precursors called leukemic blasts. Rare leukemia stem cells (LSCs) that can self-renew as well as give rise to leukemic progenitors comprising the bulk of leukemic blasts are considered the cellular reservoir of disease initiation and maintenance. LSCs are widely thought to be relatively resistant as well as adaptive to chemotherapy and can cause disease relapse. Therefore, it is imperative to understand the molecular bases of LSC forms and functions during different stages of disease progression, so we can more accurately identify these cells and design therapies to target them. Irrespective of the morphological, cytogenetic, and cellular heterogeneity of AML, the uniform, singularly important and independently significant prognosticator of disease response to therapy and patient outcome is measurable or minimal residual disease (MRD) detection, defined by residual disease detection below the morphology-based 5% blast threshold. The importance of LSC identification and frequency estimation during MRD detection, in order to make MRD more effective in predicting disease relapse and modifying therapeutic regimen is becoming increasingly apparent. This review focuses on summarizing functional and cellular composition-based LSC identification and linking those studies to current techniques of MRD detection to suggest LSC-inclusive MRD detection as well as outline outstanding questions that need to be addressed to improve the future of AML clinical management and treatment outcomes.

The Reliability of PCL/Anti-VEGF Electrospun Scaffolds to Support Limbal Stem Cells for Corneal Repair.

Since only few reported studies propose anti-vascular endothelial growth factor (anti-VEGF) delivery through electrospun scaffolds, this study greatly contributes to the potential prevention of patient's vision loss, as it explores electrospun polycaprolactone (PCL) coated with anti-VEGF for the blockage of abnormal cornea vascularization. In terms of physicochemical properties, the biological component increased the PCL scaffold fiber diameter (by ~24%) and pore area (by ~82%), while ut slightly reduced its total porosity as the anti-VEGF solution filled the voids of the microfibrous structure. The addition of the anti-VEGF increased the scaffold stiffness almost three-fold at both strains of 5 and 10%, as well as its biodegradation rate (~36% after 60 days) with a sustained release profile after Day 4 of phosphate buffered saline incubation. In terms of scaffold application function, the PCL/Anti-VEGF scaffold proved to be more favorable for the adhesion of cultured limbal stem cells (LSCs); this was confirmed by the SEM images, where the cells showed flat and elongated conformations. Further support of the LSC growth and proliferation was confirmed by the identified p63 and CK3 markers after cell staining. These results demonstrate the advantageous effect of the surface-adsorbed anti-VEGF to stop vision loss and help damaged corneal tissue repair.

Understanding the Wnt Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Feasible Key against Relapses.

Wnt signaling is a highly conserved pathway in evolution which controls important processes such as cell proliferation, differentiation and migration, both in the embryo and in the adult. Dysregulation of this pathway can favor the development of different types of cancer, such as acute myeloid leukemia and other hematological malignancies. Overactivation of this pathway may promote the transformation of pre-leukemic stem cells into acute myeloid leukemia stem cells, as well as the maintenance of their quiescent state, which confers them with self-renewal and chemoresistance capacity, favoring relapse of the disease. Although this pathway participates in the regulation of normal hematopoiesis, its requirements seem to be greater in the leukemic stem cell population. In this review, we explore the possible therapeutic targeting of Wnt to eradicate the LSCs of AML.

Evaluation of the Effect of Intravenous Dexamethasone on the Duration of Spinal Anaesthesia in Parturients Undergoing Lower Segment Caesarean Section.

Introduction Dexamethasone is shown to prolong the duration of nerve blocks when administered perineurally as well as intravenously. The effect of intravenous dexamethasone on the duration of hyperbaric bupivacaine spinal anesthesia is lesser known. We conducted a randomized control trial to determine the effect of intravenous dexamethasone on the duration of spinal anesthesia in parturients undergoing lower-segment cesarean section (LSCS). Methods Eighty parturients planned for LSCS under spinal anesthesia were randomly allocated to two groups. Patients in group A were administered dexamethasone intravenously, and group B received normal saline intravenously before spinal anesthesia. The primary objective was to determine the effect of intravenous dexamethasone on the duration of sensory and motor block after spinal anesthesia. The secondary objective was to determine the duration of analgesia and complications in both groups. Result The total duration of the sensory and motor blocks in group A was 118.38 ± 19.88 minutes and 95.63 ± 19.91 minutes, respectively. The entire sensory and motor blockade duration in group B was 116.88 ± 13.48 minutes and 97.63 ± 15.15 minutes, respectively. The difference between the groups was found to be statistically insignificant. Conclusion Intravenous 8 mg dexamethasone in patients planned for LSCS under hyperbaric spinal anesthesia does not prolong the sensory or motor block duration compared to placebo.

A Longitudinal Analytical Study on Umbilical Cord Coiling Index as a Predictor of Pregnancy Outcome.

Background The umbilical cord coiling index (UCI) is usually measured sonographically during antenatal follow-up and can be used to determine the fetuses at risk of adverse outcomes. Methodology UCI measured antenatally and postnatally whose correlation is studied along with the association of abnormal UCI with the adverse outcomes in terms of gestational age, intrauterine growth restriction (IUGR), intra-uterine death, birth weight, sex, neonatal intensive care unit (NICU) admission, the color of the liquor, Amniotic Fluid Index (AFI), Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score at one min and five mins and mode of delivery. All parameters are tested for significant differences among UCI and a p-value < 0.05 is considered significant. The correlation of UCI measured antenatally and postnatally is tested using the spearman correlation coefficient. Results A strong correlation is found between antenatal UCI and postnatal UCI with rs 0.9. The majority of the population had normo coiling. Hyper and hypo coiling are associated risks of emergency lower segment cesarean section (LSCS). Low birth weight is seen in 88.89% of hypo coiled patients with a p-value < 0.01. The coiling index among sex is found to be insignificant with a p-value of 0.81. Meconium-Stained Liquor (MSL) is seen in 78.5% of hyper coiled patients. IUGR is found to be associated with hypo coiling as seen in 59.2% of patients with significant p-value (< 0.01). Age, gestational age, and birth weight are found to be statistically significant between various coiling indexes with p-value < 0.05. Conclusion Antenatal UCI correlates with postnatal UCI and any abnormal index found can be used as a predictor of adverse perinatal outcomes and help obstetricians to monitor continuously and put the patients at risk on prophylactic measures.

Detection of Limbal Stem Cells Adhered to Melt Electrospun Silk Fibroin and Gelatin-Modified Polylactic Acid Scaffolds.

Limbal stem cells (LSCs) are of paramount importance in corneal epithelial tissue repair. The cornea becomes opaque in case of limbal stem cell deficiency (LSCD), which may cause serious damage to the ocular visual function. There are many techniques to restore damaged epithelium, one of which is the transplantation of healthy cultured LSCs, usually onto a human amniotic membrane or onto bio-based engineered scaffolds in recent years. In this study, melt electrospun polylactic acid (PLA) was modified by silk fibroin or gelatin and further cultured with LSCs originating from three different donors. In terms of physicochemical properties, both modifications slightly increased PLA scaffold porosity (with a significantly larger pore area for the PLA/gelatin) and improved the scaffolds' swelling percentage, as well as their biodegradation rate. In terms of the scaffold application function, the aim was to detect/visualize whether LSCs adhered to the scaffolds and to further determine cell viability (total number), as well as to observe p63 and CK3 expressions in the LSCs. LSCs were attached to the surface of microfibers, showing flattened conformations or 3D spheres in the formation of colonies or agglomerations, respectively. All scaffolds showed the ability to bind the cells onto the surface of individual microfibers (PLA and PLA/gelatin), or in between the microfibers (PLA/silk fibroin), with the latter showing the most intense red fluorescence of the stained cells. All scaffolds proved to be biocompatible, while the PLA/silk fibroin scaffolds showed the highest 98% viability of 2.9 × 106 LSCs, with more than 98% of p63 and less than 20% of CK3 expressions in the LSCs, thus confirming the support of their growth, proliferation and corneal epithelial differentiation. The results show the potential of these bio-engineered scaffolds to be used as an alternative clinical approach.

FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia.

BACKGROUND: Selectively targeting leukemia stem cells (LSCs) is a promising approach in treating acute myeloid leukemia (AML), for which identification of such therapeutic targets is critical. Increasing lines of evidence indicate that FBXO22 plays a critical role in solid tumor development and therapy response. However, its potential roles in leukemogenesis remain largely unknown. METHODS: We established a mixed lineage leukemia (MLL)-AF9-induced AML model with hematopoietic cell-specific FBXO22 knockout mice to elucidate the role of FBXO22 in AML progression and LSCs regulation, including self-renewal, cell cycle, apoptosis and survival analysis. Immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis, Western blotting and rescue experiments were performed to study the mechanisms underlying the oncogenic role of FBXO22. RESULTS: FBXO22 was highly expressed in AML, especially in MLL-rearranged (MLLr) AML. Upon FBXO22 knockdown, human MLLr leukemia cells presented markedly increased apoptosis. Although conditional deletion of Fbxo22 in hematopoietic cells did not significantly affect the function of hematopoietic stem cells, MLL-AF9-induced leukemogenesis was dramatically abrogated upon Fbxo22 deletion, together with remarkably reduced LSCs after serial transplantations. Mechanistically, FBXO22 promoted degradation of BACH1 in MLLr AML cells, and overexpression of BACH1 suppressed MLLr AML progression. In line with this, heterozygous deletion of BACH1 significantly reversed delayed leukemogenesis in Fbxo22-deficient mice. CONCLUSIONS: FBXO22 promotes MLLr AML progression by targeting BACH1 and targeting FBXO22 might be an ideal strategy to eradicate LSCs without influencing normal hematopoiesis.

METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism.

N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m6A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene for the survival of acute myeloid leukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16 is aberrantly overexpressed in human AML cells, especially in leukemia stem cells (LSCs) and leukemia-initiating cells (LICs). Genetic depletion of METTL16 dramatically suppresses AML initiation/development and maintenance and significantly attenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesis in mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m6A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m6A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m6A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.