GATA6 Suppresses Lung Adenocarcinoma Progression by Activating CFTR to Modulate Arachidonic Acid Metabolism.

BACKGROUND: CFTR, which belongs to the ATP-binding cassette transporter family and whose members are always involved in cancer progression, is implicated in lung adenocarcinoma (LUAD) progression, but the underlying mechanism remains undefined. Therefore, this study intended to investigate how CFTR works exactly on LUAD progression. METHODS: Bioinformatics methods were utilized to analyze GATA6 and CFTR expression in LUAD and targeting relationship, followed by a pathway enrichment analysis of CFTR. GATA6 and CFTR expression levels were assessed by qRT-PCR. Cell viability and proliferation were detected through MTT and colony formation assays. An arachidonic acid (AA) assay kit was utilized to measure AA content. mRNA and protein expression levels of genes (cPLA2, COX-2, and CYP1A1) related to the AA metabolism pathway were detected by qRT-PCR and western blot, respectively. Moreover, the Dual-luciferase reporter gene assay and ChIP were used to verify the binding of GATA6 and CFTR promoters. RESULTS: GATA6 and CFTR were lowly expressed in LUAD, and CFTR was enriched in the AA metabolism pathway. GATA6 activated CFTR transcription. Cellular and rescue experiments revealed that low or high CFTR expression could foster or hamper LUAD cell viability and proliferation, and concomitant treatment of indomethacin, an AA metabolism pathway inhibitor, mitigated stimulation on LUAD progression by low CFTR expression. Silencing of GATA6 reversed the suppressive impact of CFTR overexpression on LUAD progression via modulation of the AA metabolism pathway. CONCLUSION: The activation of CFTR by GATA6 hampered LUAD progression by modulating the AA metabolism pathway, suggesting that GATA6/CFTR axis might be a therapeutic target for LUAD patients.

Identification of a Prognostic Gene Signature Based on Lipid Metabolism-Related Genes in Esophageal Squamous Cell Carcinoma.

Background: Dysregulation of lipid metabolism is common in cancer. However, the molecular mechanism underlying lipid metabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are not well understood. The objective of our study was to construct a lipid metabolism-related prognostic model to improve prognosis prediction in ESCC. Methods: We downloaded the mRNA expression profiles and corresponding survival data of patients with ESCC from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. We performed differential expression analysis to identify differentially expressed lipid metabolism-related genes (DELMGs). We used Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses to establish a risk model in the GEO cohort and used data of patients with ESCC from the TCGA cohort for validation. We also explored the relationship between the risk model and the immune microenvironment via infiltrated immune cells and immune checkpoints. Results: The result showed that 132 unique DELMGs distinguished patients with ESCC from the controls. We identified four genes (ACAA1, ACOT11, B4GALNT1, and DDHD1) as prognostic gene expression signatures to construct a risk model. Patients were classified into high- and low-risk groups as per the signature-based risk score. We used the receiver operating characteristic (ROC) curve and the Kaplan-Meier (KM) survival analysis to validate the predictive performance of the 4-gene signature in both the training and validation sets. Infiltrated immune cells and immune checkpoints indicated a difference in the immune status between the two risk groups. Conclusion: The results of our study indicated that a prognostic model based on the 4-gene signature related to lipid metabolism was useful for the prediction of prognosis in patients with ESCC.

Nomogram-based prediction model for survival of COVID-19 patients: A clinical study.

The study aim to construct an effective model for predicting the survival period of COVID-19 patients. METHODS: Clinical data of 386 COVID-19 patients were collected from December 2022 to January 2023. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. LASSO regression and multivariate Cox regression analyses were used to identify prognostic factors, and a nomogram was constructed. Nomogram was evaluated using decision curve analysis, receiver operating characteristic curve, consistency index (c-index), and calibration curve. RESULTS: 86 patients (22.3%) died. A new nomogram for predicting the survival was established based on age, resting oxygen saturation, Blood urea nitrogen (BUN), c-reactive protein-to-albumin ratio (CAR), and pneumonia visual score. The decision curve indicated high clinical applicability. The nomogram c-indexes in the training and validation cohorts were 0.846 and 0.81, respectively. The area under the curves (AUCs) for the 15-day and 30-day survival probabilities were 0.906 and 0.869 in the training cohort, and 0.851 and 0.843 in the validation cohort. The calibration curves demonstrated consistency between predicted and actual survival probabilities. CONCLUSIONS: Our nomogram has the capacity to assist clinical practitioners in estimating the survival rate of COVID-19 patients, thereby facilitating more optimal management strategies and therapeutic interventions with substantial clinical applicability.

Single Crystals of Insoluble Porous Salicylimine Cages.

Porous organic cages (POCs) are meanwhile an established class of porous materials. Most of them are soluble to a certain extend and thus processable in or from solution. However, a few of larger salicylimine cages were reported to be insoluble in any organic solvents and thus characterized as amorphous materials. These cages were now synthesized as single-crystalline materials to get insight into packing motifs and preferred intermolecular interactions. Furthermore, the pairs of crystalline and amorphous materials for each cage allowed to compare their gas-sorption properties in both morphological states.

Expansion of human megakaryocyte-biased hematopoietic stem cells by biomimetic Microniche.

Limited numbers of available hematopoietic stem cells (HSCs) limit the widespread use of HSC-based therapies. Expansion systems for functional heterogenous HSCs remain to be optimized. Here, we present a convenient strategy for human HSC expansion based on a biomimetic Microniche. After demonstrating the expansion of HSC from different sources, we find that our Microniche-based system expands the therapeutically attractive megakaryocyte-biased HSC. We demonstrate scalable HSC expansion by applying this strategy in a stirred bioreactor. Moreover, we identify that the functional human megakaryocyte-biased HSCs are enriched in the CD34+CD38-CD45RA-CD90+CD49f lowCD62L-CD133+ subpopulation. Specifically, the expansion of megakaryocyte-biased HSCs is supported by a biomimetic niche-like microenvironment, which generates a suitable cytokine milieu and supplies the appropriate physical scaffolding. Thus, beyond clarifying the existence and immuno-phenotype of human megakaryocyte-biased HSC, our study demonstrates a flexible human HSC expansion strategy that could help realize the strong clinical promise of HSC-based therapies.

MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis.

Conventional chemotherapy for killing cancer cells using cytotoxic drugs suffers from low selectivity, significant toxicity, and a narrow therapeutic index. Hyper-specific targeted drugs achieve precise destruction of tumors by inhibiting molecular pathways that are critical to tumor growth. Myeloid cell leukemia 1 (MCL-1), an important pro-survival protein in the BCL-2 family, is a promising antitumor target. In this study, we chose to investigate the effects of S63845, a small-molecule inhibitor that targets MCL-1, on the normal hematopoietic system. A mouse model of hematopoietic injury was constructed, and the effects of the inhibitor on the hematopoietic system of mice were evaluated via routine blood tests and flow cytometry. The results showed that S63845 affected the hematopoiesis of various lineages in the early stage of action, causing extramedullary compensatory hematopoiesis in the myeloid and megakaryocytic lineages. The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. This study provides a complete description of the effects of MCL-1 inhibitor on the intramedullary and extramedullary hematopoietic lineages, which is important for the selection of combinations of antitumor drugs and the prevention of adverse hematopoiesis-related effects.

KDM4 inhibitor SD49-7 attenuates leukemia stem cell via KDM4A/MDM2/p21CIP1 axis.

Rationale: Traditional treatments for leukemia fail to address stem cell drug resistance characterized by epigenetic mediators such as histone lysine-specific demethylase 4 (KDM4). The KDM4 family, which acts as epigenetic regulators inducing histone demethylation during the development and progression of leukemia, lacks specific molecular inhibitors. Methods: The KDM4 inhibitor, SD49-7, was synthesized and purified based on acyl hydrazone Schiff base. The interaction between SD49-7 and KDM4s was monitored in vitro by surface plasma resonance (SPR). In vitro and in vivo biological function experiments were performed to analyze apoptosis, colony-formation, proliferation, differentiation, and cell cycle in cell sub-lines and mice. Molecular mechanisms were demonstrated by RNA-seq, ChIP-seq, RT-qPCR and Western blotting. Results: We found significantly high KDM4A expression levels in several human leukemia subtypes. The knockdown of KDM4s inhibited leukemogenesis in the MLL-AF9 leukemia mouse model but did not affect the survival of normal human hematopoietic cells. We identified SD49-7 as a selective KDM4 inhibitor that impaired the progression of leukemia stem cells (LSCs) in vitro. SD49-7 suppressed leukemia development in the mouse model and patient-derived xenograft model of leukemia. Depletion of KDM4s activated the apoptosis signaling pathway by suppressing MDM2 expression via modulating H3K9me3 levels on the MDM2 promoter region. Conclusion: Our study demonstrates a unique KDM4 inhibitor for LSCs to overcome the resistance to traditional treatment and offers KDM4 inhibition as a promising strategy for resistant leukemia therapy.

Highly Selective Adsorption of Perfluorinated Greenhouse Gases by Porous Organic Cages.

Anthropogenic greenhouse gases contribute to global warming. Among those gases, perfluorocarbons (PFCs) are thousands to tens of thousands of times more harmful to the environment than comparable amounts of carbon dioxide. To date, materials that selectively adsorb perfluorocarbons in favor of other less harmful gases have not been reported. Here, a series of porous organic cage compounds with alkyl-, fluoroalkyl-, and partially fluorinated alkyl groups is presented. Their isomorphic crystalline states allow the study of the structure-property relationship between the degree of fluorination of the alkyl chains and the gas sorption properties for PFCs and their selective uptakes in comparison to other, nonfluorinated gases. By this approach, one compound having superior selectivities of PFCs versus N2 or CO2 under ambient conditions is identified.

Allele segregation analysis of F1 hybrids between independent Brassica allohexaploid lineages.

In the Brassica genus, we find both diploid species (one genome) and allotetraploid species (two different genomes) but no naturally occurring hexaploid species (three different genomes, AABBCC). Although hexaploids can be produced via human intervention, these neo-polyploids have quite unstable genomes and usually suffer from severe genome reshuffling. Whether these genome rearrangements continue in later generations and whether genomic arrangements follow similar, reproducible patterns between different lineages is still unknown. We crossed Brassica hexaploids resulting from different species combinations to produce five F1 hybrids and analyzed the karyotypes of the parents and the F1 hybrids, as well as allele segregation in a resulting test-cross population via molecular karyotyping using SNP array genotyping. Although some genomic regions were found to be more likely to be duplicated, deleted, or rearranged, a consensus pattern was not shared between genotypes. Brassica hexaploids had a high tolerance for fixed structural rearrangements, but which rearrangements occur and become fixed over many generations does not seem to show either strong reproducibility or to indicate selection for stability. On average, we observed 10 de novo chromosome rearrangements contributed almost equally from both parents to the F1 hybrids. At the same time, the F1 hybrid meiosis produced on average 8.6 new rearrangements. Hence, the increased heterozygosity in the F1 hybrid did not significantly improve genome stability in our hexaploid hybrids and might have had the opposite effect. However, hybridization between lineages was readily achieved and may be exploited for future genetics and breeding purposes.

Levistilide A Promotes Expansion of Human Umbilical Cord Blood Hematopoietic Stem Cells by Enhancing Antioxidant Activity.

Several approaches to expand human hematopoietic stem cells (hHSCs) clinically along with retainable capability of multipotential differentiation have been reported, but only a few have advanced to evaluation in clinical trials, which limits the application of HSC-based therapy. Here we show a phthalide derivative, Levistilide A (LA), can serve as a promising molecule to expand functional human umbilical cord blood (UCB) HSCs ex vivo. An in-house screen identified LA out of nine natural products as an outstanding candidate for hHSCs expansion. Additionally, our data indicated that LA treatment not only increased the numbers of phenotype-defined HSCs, but also enhanced their colony formation ability. Xenotransplantation assays showed that LA treatment could maintain unaffected engraftment of hHSCs with multilineage differentiation capacity. Further experiments revealed that LA enhanced the antioxidant activity of hHSCs by reducing intracellular and mitochondrial reactive oxygen species (ROS) levels. The identification of LA provides a new strategy in solving the clinical issue of limited numbers of UCB HSCs.

Epigenetic study of early breast cancer (EBC) based on DNA methylation and gene integration analysis.

Breast cancer (BC) is one of the leading causes of cancer-related deaths in women. The purpose of this study is to identify key molecular markers related to the diagnosis and prognosis of early breast cancer (EBC). The data of mRNA, lncRNA and DNA methylation were downloaded from The Cancer Genome Atlas (TCGA) dataset for identification of differentially expressed mRNAs (DEmRNAs), differentially expressed lncRNAs (DElncRNAs) and DNA methylation analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzes were used to identify the biological functions of DEmRNAs. The correlation analysis between DNA methylation and DEmRNAs was carried out. Then, diagnostic analysis and prognostic analysis of identified DEmRNAs and DElncRNAs were also performed in the TCGA database. Subsequently, methylation state verification for identified DEmRNAs was performed in the GSE32393 dataset. In addition, real-time polymerase chain reaction (RT-PCR) in vitro verification of genes was performed. Finally, AC093110.1 was overexpressed in human BC cell line MCF-7 to verify cell proliferation and migration. In this study, a total of 1633 DEmRNAs, 750 DElncRNAs and 8042 differentially methylated sites were obtained, respectively. In the Venn analysis, 11 keys DEmRNAs (ALDH1L1, SPTBN1, MRGPRF, CAV2, HSPB6, PITX1, WDR86, PENK, CACNA1H, ALDH1A2 and MME) were we found. ALDH1A2, ALDH1L1, HSPB6, MME, MRGPRF, PENK, PITX1, SPTBN1, WDR86 and CAV2 may be considered as potential diagnostic gene biomarkers in EBC. Strikingly, CAV2, MME, AC093110.1 and AC120498.6 were significantly actively correlated with survival. Methylation state of identified DEmRNAs in GSE32393 dataset was consistent with the result in TCGA. AC093110.1 can affect the proliferation and migration of MCF-7. ALDH1A2, ALDH1L1, HSPB6, MME, MRGPRF, PENK, PITX1, SPTBN1, WDR86 and CAV2 may be potential diagnostic gene biomarkers of EBC. Strikingly, CAV2, MME, AC093110.1 and AC120498.6 were significantly actively correlated with survival. The identification of these genes can help in the early diagnosis and treatment of EBC. In addition, AC093110.1 can regulate SPTBN1 expression and play an important role in cell proliferation and migration, which provides clues to clarify the regulatory mechanism of EBC.

Enhanced self-renewal of human long-term hematopoietic stem cells by a sulfamoyl benzoate derivative targeting p18INK4C.

The use of umbilical cord blood transplant has been substantially limited by the finite number of hematopoietic stem and progenitor cells in a single umbilical cord blood unit. Small molecules that not only quantitatively but also qualitatively stimulate enhancement of hematopoietic stem cell (HSC) self-renewal ex vivo should facilitate the clinical use of HSC transplantation and gene therapy. Recent evidence has suggested that the cyclin-dependent kinase inhibitor, p18INK4C (p18), is a critical regulator of mice HSC self-renewal. The role of p18 in human HSCs and the effect of p18 inhibitor on human HSC expansion ex vivo need further studies. Here we report that knockdown of p18 allowed for an increase in long-term colony-forming cells in vitro. We then identified an optimized small molecule inhibitor of p18, 005A, to induce ex vivo expansion of HSCs that was capable of reconstituting human hematopoiesis for at least 4 months in immunocompromised mice, and hence, similarly reconstituted secondary recipients for at least 4 more months, indicating that cells exposed to 005A were still competent in secondary recipients. Mechanistic studies showed that 005A might delay cell division and activate both the Notch signaling pathway and expression of transcription factor HoxB4, leading to enhancement of the self-renewal of long-term engrafting HSCs and the pool of progenitor cells. Taken together, these observations support a role for p18 in human HSC maintenance and that the p18 inhibitor 005A can enhance the self-renewal of long-term HSCs.

[The Effect and Mechanism of Novel Telomerase Inhibitor Nilo 22 on Leukemia Cells].

OBJECTIVE: To investigate the cytotoxic effect and its mechanism of the micromolecule compound on the leukemia cells. METHODS: The cytotoxic effects of 28 Nilotinib derivatives on K562, KA, KG, HA and 32D cell lines were detected by MTT assays, and the compound Nilo 22 was screen out. Cell apoptosis and cell cycle on leukemia cells were detected by flow cytometry. The effect of compound screened out on leukemogenesis potential of MLL-AF9 leukemia mice GFP+ cells was tested by colony-forming units assays (CFU). The cytotoxic effect was further detected by transplant assays ex vivo. Telomerase activity assay, C-circle assay were used to measure the effects of compound on the length mechanism of telomere, RT-PCR was used to detected the changes of telomere. RESULTS: Nilo 22 serves as the most outstanding candidate out of 28 Nilotinib derivatives, which impairs leukemia cell lines, but spares normal hematopoietic cell line. Comparing with Nilotinib, Nilo 22 could induce the apoptosis of GFP+ cells significantly, slightly arrests the cell cycle at G0/G1 phase, and significantly inhibits colony formation and prolong the progression in MLL-AF9 leukemia mice model. The expression showed that the compound could slow the disease progression in MLL-AF9 leukemia mice significantly. Mechanistically, Nilo 22 could reduce the length of telomere by inhibiting telomerase activity and alternative lengthening of telomere (ALT). CONCLUSION: Nilo 22 shows a significant cytotoxic effect on mice and human leukemia cells, especially for drug resistance cells. Nilo 22 is a promising anti-leukemia agent to solve the common clinical problems of drug resistance and relapse of leukemia.

Dexmedetomidine attenuates neuronal injury induced by cerebral ischemia­reperfusion by regulating miR­199a.

As is well known, dexmedetomidine (DEX) serves a neuroprotective role in cerebral ischemia­reperfusion (CIR) injury, and microRNA (miR)­199a has been re­ported to be associated with IR injury. However, the association between DEX and miR­199a in CIR injury remains unknown. Thus, the aim of the present study was to verify whether the neuroprotective effect of DEX on cerebral ischemia­reperfusion rats is associated with miR­199a. A rat model of CIR was established, and the modified neurological severity score (mNSS) was evaluated. The effect of DEX on the patholog­ical structure of the cerebral cortex in CIR rats was observed by hematoxylin and eosin and Nissl staining. Reverse transcription­quantitative PCR was used to analyze the expression levels of miR­199a in brain tissue following intracerebroventricular injection of miR­199a antagomir. The co­expression of NeuN and microtubule­associated proteins 1A/1B light chain 3B in the cerebral cortex was analyzed by immunofluorescence staining. Western blotting and immunohistochemistry were performed to analyze the expression of autophagy­associated proteins in the brain tissue. DEX inhibited the expression of miR­199a, decreased the mNSS and improved pathological damage to the cerebral cortex. DEX also inhibited autophagy and expression levels of associated proteins and decreased nerve cell injury. In conclusion, DEX inhibited expression of miR­199a and improved neurocyte injury induced by CIR.

A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells.

There has been an increasing focus on the tumorigenic potential of leukemia initiating cells (LICs) in acute myeloid leukemia (AML). Despite the important role of selective autophagy in the life-long maintenance of hematopoietic stem cells (HSCs), cancer progression, and chemoresistance, the relationship between LICs and selective autophagy remains to be fully elucidated. Sequestosome 1 (SQSTM1), also known as p62, is a selective autophagy receptor for the degradation of ubiquitinated substrates, and its loss impairs leukemia progression in AML mouse models. In this study, we evaluated the underlying mechanisms of mitophagy in the survival of LICs with XRK3F2, a p62-ZZ inhibitor. We demonstrated that XRK3F2 selectively impaired LICs but spared normal HSCs in both mouse and patient-derived tumor xenograft (PDX) AML models. Mechanistically, we observed that XRK3F2 blocked mitophagy by inhibiting the binding of p62 with defective mitochondria. Our study not only evaluated the effectiveness and safety of XRK3F2 in LICs, but also demonstrated that mitophagy plays an indispensable role in the survival of LICs during AML development and progression, which can be impaired by blocking p62.

Chiral Self-sorting of Giant Cubic [8+12] Salicylimine Cage Compounds.

Chiral self-sorting is intricately connected to the complicated chiral processes observed in nature and no artificial systems of comparably complexity have been generated by chemists. However, only a few examples of purely organic molecules have been reported so far, where the self-sorting process could be controlled. Herein, we describe the chiral self-sorting of large cubic [8+12] salicylimine cage compounds based on a chiral TBTQ precursor. Out of 23 possible cage isomers only the enantiopure and a meso cage were observed to be formed, which have been unambiguously characterized by single crystal X-ray diffraction. Furthermore, by careful choice of solvent the formation of meso cage could be controlled. With internal diameters of din =3.3-3.5 nm these cages are among the largest organic cage compounds characterized and show very high specific surface areas up to approx. 1500 m2 g-1 after desolvation.

Phytotoxicity of Y2O3 nanoparticles and Y3+ ions on rice seedlings under hydroponic culture.

Due to the characteristics of both rare earth elements (REEs) and nanoparticles (NPs), Y2O3 NPs have been widely used in the fields of medicine, military industry, and agriculture, especially in the areas of electricity, light, magnetism, and catalysis. Given this widespread use, it is inevitable that Y2O3 NPs and soluble Y3+ will enter bodies of water through the processes involved in their preparation, application, and disposal. We sought to investigate the toxicities of Y2O3 NPs and Y3+ ions on rice seedlings (Oryza sativa L.), as well as the uptake and distribution of Y2O3 NPs under hydroponic conditions. Our results indicated that Y2O3 NPs and released Y3+ had no significant effect on the germination rate of rice. However, high concentrations of Y2O3 NPs (50 and 100 mg/L) delayed seed germination. As for rice root elongation, low concentrations (1, 5, and 10 mg/L) of Y2O3 NPs had a positive effect. Notably, when Y2O3 NPs concentration reached 20 mg/L and higher, root elongation was significantly inhibited. According to the physiological and biochemical characteristics of rice seedlings under Y stress, Y2O3 NPs ranging from 20 to 100 mg/L significantly reduced chlorophyll contents and root activity. Using ICP-MS and TEM analyses, Y2O3 NPs and Y3+ were shown to be mainly absorbed and accumulated in the roots. With Y2O3 NPs exposure, the Y transport coefficient from the roots to the shoots of rice was 1.94-7.55%. Comparatively, Y3+ ions had an insignificant effect on plant growth, with the phytotoxicity of Y being mainly produced by Y2O3 NPs.

A Robust Porous Quinoline Cage: Transformation of a [4+6] Salicylimine Cage by Povarov Cyclization.

Porous shape-persistent organic cages have become the object of interest in recent years because they are soluble and thus processable from solution. A variety of cages can be achieved by applying dynamic covalent chemistry (DCC), but they are less chemically stable. Here the transformation of a salicylimine cage into a quinoline cage by a twelve-fold Povarov reaction as the key step is described. Besides the chemical stability of the cage over a broad pH regime, it shows a unique absorption and emission depending on acid concentration. Furthermore, thin films for the vapor detection of acids were investigated, showing color switches from pale-yellow to red, and characteristic emission profiles.

A small molecule compound IX inhibits telomere and attenuates oncogenesis of drug-resistant leukemia cells.

Drug resistance is a common obstacle in leukemia treatment and failing to eradicate leukemia stem cells is the main cause of leukemia relapse. Previous studies have demonstrated that telomerase activity is associated with deregulated self-renewal of leukemia stem cells (LSCs). Here, we identified a novel compound IX, an imatinib derivative with a replacement fragment of a telomerase inhibitor, which can effectively eradicate LSCs but had no influence on normal hematopoietic stem cells (HSCs) survival. We showed that compound IX can decrease the viability of drug-resistant K562/G cells and blast crisis CML primary patient cells. Besides, IX can affect LSC survival, inhibit the colony-forming ability, and reduce LSC frequency. In vivo results showed that IX can relieve the tumor burden in patient-derived xenograft (PDX) model and prolong the lifespan. We observed that compound IX can not only decrease telomerase activity, but also affect the alternative lengthening of telomeres. In addition, IX can inhibit both the canonical and non-canonical Wnt pathways. Our data suggested this novel compound IX as a promising candidate for drug-resistant leukemia therapy.