RESUMEN
The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
Asunto(s)
Proteína 7 Similar a la Angiopoyetina , Proteína 1 Inhibidora de la Diferenciación , Leucemia Mieloide Aguda , Animales , Ratones , Proteína 7 Similar a la Angiopoyetina/genética , Proteína 7 Similar a la Angiopoyetina/metabolismo , Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Microambiente Tumoral , Humanos , Proteína 1 Inhibidora de la Diferenciación/metabolismoRESUMEN
SETD2, the histone H3 lysine 36 methyltransferase, previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in myelodysplastic syndromes (MDSs) has been unclear. In this study, low expression of SETD2 correlated with shortened survival in patients with MDS, and the SETD2 levels in CD34+ bone marrow cells of those patients were increased by decitabine. We knocked out Setd2 in NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and found that loss of Setd2 accelerated the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhanced the ability of NHD13+ hematopoietic stem and progenitor cells (HSPCs) to self-renew, with increased symmetric self-renewal division and decreased differentiation and cell death. The growth of MDS-associated leukemia cells was inhibited though increasing the H3K36me3 level by using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulated hematopoietic stem cell signaling and downregulated myeloid differentiation pathways in the NHD13+ HSPCs. Our RNA-seq and chromatin immunoprecipitation-seq analysis indicated that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in the NHD13+ HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, including Ikba and Jnk, which influence the self-renewal and differentiation of HSPCs. Therefore, our results demonstrated that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.
Asunto(s)
Anemia Refractaria con Exceso de Blastos/patología , Calgranulina B/fisiología , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/fisiología , Leucemia Mieloide Aguda/etiología , Anemia Refractaria con Exceso de Blastos/genética , Anemia Refractaria con Exceso de Blastos/metabolismo , Animales , Calgranulina B/biosíntesis , Calgranulina B/genética , Transformación Celular Neoplásica , Células Cultivadas , Decitabina/farmacología , Regulación hacia Abajo , Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Código de Histonas/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/biosíntesis , N-Metiltransferasa de Histona-Lisina/genética , Proteínas de Homeodominio/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Síndromes Mielodisplásicos/patología , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Pronóstico , Proteínas Recombinantes/uso terapéutico , Factores de Tiempo , Análisis de Matrices Tisulares , TranscriptomaRESUMEN
Acid-base bifunctional heterogeneous solid catalysts, known as the active site with base-acid properties, exhibited relatively good performance on the transesterification for soybean oil for green fuel production. We investigated the use of niobium and three alkali metal oxides (Li, Na, and K) as MyNbOX (M = Li, Na, K) composite as acid-base catalysts for biodiesel production. MyNbOX catalysts were prepared using a simple solid-state reaction, mixing, and grinding niobium dioxide with alkali metal carbonates calcined at 800 °C in air for 4 h. XRD, BET, FE-SEM, TEM and TPD techniques were employed for catalysts characterization. The highest biodiesel yield (98.08%) was achieved under the transesterification condition of 65 °C, 6 h, 24 methanol/oil molar ratio and 2 wt% of LiNbO3 as the catalyst. The results showed that LiNbO3 could be efficiently reused at least 10 cycles with an insignificant reduction in the biodiesel yield. The physicochemical properties of the biodiesel were further studied and compared with the ASTM and the EN biodiesel specifications. The results showed that the properties of the biodiesel produced complied with the international standard specifications.
Asunto(s)
Biocombustibles , Aceite de Soja , Catálisis , Esterificación , MetanolRESUMEN
A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.
Asunto(s)
Fructosa , Humanos , Animales , Ratones , Fructosa/metabolismo , Cromatina/metabolismo , Aldehído Reductasa/metabolismo , Aldehído Reductasa/genética , Leucemia/metabolismo , Leucemia/patología , Leucemia/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Ensamble y Desensamble de Cromatina , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinogénesis/genética , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Adenosina TrifosfatasasRESUMEN
The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.
Asunto(s)
Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Animales , Ratones , Humanos , Rituximab/uso terapéutico , Pimozida/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma no Hodgkin/tratamiento farmacológico , Proteasas Ubiquitina-Específicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.
Asunto(s)
Eritropoyesis , Síndromes Mielodisplásicos , Animales , Humanos , Ratones , Eritropoyesis/genética , Síndromes Mielodisplásicos/genética , Proteínas del Tejido Nervioso/genética , Pronóstico , Receptores Inmunológicos/genética , Proteínas RoundaboutRESUMEN
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Carcinogénesis , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Histona Desacetilasas , Leucemia Mieloide Aguda/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
In this study, long-term continuous monitoring of atmospheric new particle formation was conducted from 2015 to 2017 in the Shanghai suburbs using a scanning mobility particle sizer (SMPS). Combined with meteorological parameters, gaseous pollutants, and PM2.5 chemical composition data, the characterization of new particle formation was analyzed. The results of data analysis showed there were 172 new particle formation (NPF) days in the Shanghai suburbs, accounting for 18.3% of the total effective days (942 d). Typical new particle formation days (Event) and new particle growth-shrinkage (Shrinkage) days were 150 d and 32 d, respectively. The frequency of NPF occurrence was the highest in spring and summer, followed by autumn and winter. Compared with non-new particle formation (Non-NPF) days, Event and Shrinkage days had higher temperature and wind speed, lower humidity, less rainfall, and stronger solar radiation. The ratio of Event days was the highest when the prevailing wind was southerly, southwesterly, or westerly, and when the air masses were mainly from the vegetation cover and agricultural planting areas in the Taihu Lake Basin. The prevailing wind directions for Non-NPF and Shrinkage days were northeasterly and easterly to southeasterly. On the Event days, SO2 and O3 were higher than that on the Non-NPF days, indicating gaseous sulfuric acid and photochemical reactions were key contributors to new particle formation. Higher PM10 concentration was detected on the Event days than on the Non-NPF days, which may be attributed to the photocatalytic reaction. All the pollutant concentrations were the lowest on Shrinkage days, except that of O3. The average concentrations of inorganic components of PM2.5, such as NH4+, SO42-, and NO3- were higher on Event than on Non-NPF days in fall, whereas the opposite results were observed in other seasons. The average concentration of organic carbon on Event days was higher than that on Non-NPF days in each season. The concentrations of PM2.5 components on Shrinkage days were the lowest. However, the ratio of organic carbon on Shrinkage days was higher than that on Non-NPF days in spring, summer, and winter. The higher ratio of organic carbon on the NPF days than on the Non-NPF days suggested an important role of organic matter in the formation and growth of new particles in the suburbs of Shanghai.
RESUMEN
BACKGROUND: The most common mechanisms of multidrug resistance (MDR) in cancer cells is the expression of an energy-dependent exfflux pump. P-glycoprotein (P-gp) encoded by MDR1 gene and multidrug associated protein (MRP) are well known proteins associated with MDR. In human cancers, the MDR1 gene expression is common in patients with intrinsic and acquired MDR. It is a major therapeutic problem in cancer chemotherapy. Previously we found that the MDR of HCC is related to MRP gene expression and initiates the intrinsic MDR. The aim of this study is to study the expression of MDR1 gene encoding P-gp and MDRl mRNA in primary gallbladder carcinoma, and analyze its clinical significance. METHODS: Immunohistochemistry (IHC) S-P method and in situ polymerase chain reaction (ISPCR) were used to detect the expression of P-gp and MDR1 mRNA in 53 cases of untreated primary gallbladder carcinoma and 12 cases of cholecystitis (archival paraffin-embedded tissues). RESULTS: The positive expression rates of P-gp and MDR1 mRNA in the 53 cases and 12 cases were 60.38%, 71.69% and 25.00%, 33.33%, respectively. There was a significant difference between the two groups (P<0.05). The positive expression rate of P-gp and MDR1mRNA were 69.44%, 83.33% and 41.18%, 47.06% respectively in tissues in stage of Nevin I-III against Nevin IV, V (P<0.05). In well, moderately differentiated gallbladder carcinoma tissues, their expressions were 79.49%, 69.23% against 50.00%, 35.71% in low, undifferentiated tissues (P<0.05). CONCLUSIONS: MDR to gallbladder carcinoma is closely related to the intrinsic MDR and it provides an important evidence to reverse the MDR by detection of the MDR1 gene. Meanwhile, MDR1 gene expression in gallbladder carcinoma is correlated with some biological characteristics, takes part in the carcinogenesis of gallbladder tissues, and acts as a valuable biomarker of prognosis.