RESUMEN
The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Gluconatos/metabolismo , Neoplasias/enzimología , Proteína Fosfatasa 2/metabolismo , Células A549 , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Proliferación Celular , Activación Enzimática , Glucosafosfato Deshidrogenasa/genética , Glucosafosfato Deshidrogenasa/metabolismo , Células HEK293 , Células HT29 , Humanos , Células K562 , Células MCF-7 , Ratones Desnudos , Neoplasias/genética , Neoplasias/patología , Células PC-3 , Vía de Pentosa Fosfato , Unión Proteica , Proteína Fosfatasa 2/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ribulosafosfatos/metabolismo , Transducción de Señal , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Carga Tumoral , Familia-src Quinasas/metabolismoRESUMEN
Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors. Mechanistically, chondroitin sulfate glucuronyltransferase (CSGlcA-T) signals through its product CHSA to enhance casein kinase 2 (CK2)-PTEN binding and consequent phosphorylation and inhibition of PTEN, which requires CHSA chains and is essential to sustain AKT activation in BRAF V600E-expressing melanoma cells. However, this CHSA-dependent PTEN inhibition is dispensable in cancer cells expressing mutant NRAS or PI3KCA, which directly activate the PI3K-AKT pathway. These results suggest that dietary supplements may exhibit oncogene-dependent pro-tumor effects.
Asunto(s)
Carcinógenos/toxicidad , Transformación Celular Neoplásica/genética , Sulfatos de Condroitina/toxicidad , Suplementos Dietéticos/toxicidad , Melanoma/inducido químicamente , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/inducido químicamente , Animales , Antinematodos/farmacología , Quinasa de la Caseína II/metabolismo , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , GTP Fosfohidrolasas/genética , Células HEK293 , Células HT29 , Humanos , Melanoma/tratamiento farmacológico , Melanoma/enzimología , Melanoma/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones Transgénicos , Células 3T3 NIH , Proteínas Nucleares/genética , Fosfohidrolasa PTEN/antagonistas & inhibidores , Fosfohidrolasa PTEN/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Factores de Transcripción/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is "hijacked" to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.
Asunto(s)
Acetil-CoA C-Acetiltransferasa/metabolismo , Mitocondrias/enzimología , Complejo Piruvato Deshidrogenasa/metabolismo , Acetil-CoA C-Acetiltransferasa/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Factor de Crecimiento Epidérmico/metabolismo , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , Células 3T3 NIH , Neoplasias/enzimología , Neoplasias/patología , Oligopéptidos/genética , Oligopéptidos/metabolismo , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismoRESUMEN
Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years. Although many human cancers share similar metabolic alterations, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Using an RNAi-based screen targeting the majority of the known metabolic proteins, we recently found that oncogenic BRAFV600E up-regulates HMG-CoA lyase (HMGCL), which converts HMG-CoA to acetyl-CoA and a ketone body, acetoacetate, that selectively enhances BRAFV600E-dependent MEK1 activation in human cancer. Here, we identified HMG-CoA synthase 1 (HMGCS1), the upstream ketogenic enzyme of HMGCL, as an additional "synthetic lethal" partner of BRAFV600E Although HMGCS1 expression did not correlate with BRAFV600E mutation in human melanoma cells, HMGCS1 was selectively important for proliferation of BRAFV600E-positive melanoma and colon cancer cells but not control cells harboring active N/KRAS mutants, and stable knockdown of HMGCS1 only attenuated colony formation and tumor growth potential of BRAFV600E melanoma cells. Moreover, cytosolic HMGCS1 that co-localized with HMGCL and BRAFV600E was more important than the mitochondrial HMGCS2 isoform in BRAFV600E-expressing cancer cells in terms of acetoacetate production. Interestingly, HMGCL knockdown did not affect HMGCS1 expression levels, whereas HMGCS1 knockdown caused a compensating increase in HMGCL protein level because of attenuated protein degradation. However, this increase did not reverse the reduced ketogenesis in HMGCS1 knockdown cells. Mechanistically, HMGCS1 inhibition decreased intracellular acetoacetate levels, leading to reduced BRAFV600E-MEK1 binding and consequent MEK1 activation. We conclude that the ketogenic HMGCS1-HMGCL-acetoacetate axis may represent a promising therapeutic target for managing BRAFV600E-positive human cancers.
Asunto(s)
Neoplasias del Colon/enzimología , Hidroximetilglutaril-CoA Sintasa/metabolismo , MAP Quinasa Quinasa 1/metabolismo , Melanoma/enzimología , Proteínas de Neoplasias/metabolismo , Oxo-Ácido-Liasas/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Acetoacetatos/metabolismo , Sustitución de Aminoácidos , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Citosol/enzimología , Citosol/metabolismo , Activación Enzimática , Estabilidad de Enzimas , Femenino , Humanos , Hidroximetilglutaril-CoA Sintasa/antagonistas & inhibidores , Hidroximetilglutaril-CoA Sintasa/genética , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , MAP Quinasa Quinasa 1/química , Melanoma/metabolismo , Melanoma/patología , Ratones Desnudos , Mutación , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Oxo-Ácido-Liasas/antagonistas & inhibidores , Oxo-Ácido-Liasas/química , Oxo-Ácido-Liasas/genética , Proteolisis , Proteínas Proto-Oncogénicas B-raf/genética , Interferencia de ARN , Carga TumoralRESUMEN
Myeloid sarcoma (MS) occurs in patients with acute myeloid leukemia (AML). In rare cases, MS can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), myelodysplastic neoplasms (MDS), or MDS/MPN. The most frequent chromosomal alterations in MS are t(8;21) or inv(16), with other alterations being reported. Cases of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis are exceedingly rare. Here, we describe such a case. To the best of our knowledge, this is the first report of a JAK2 V617F mutation-positive MDS case occurring concurrently with MS involving the posterior aspect of the left seventh rib. No clear association has been previously demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. Interestingly, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation. Following a treatment regimen of azacitidine and venetoclax, the patient achieved complete remission. The chest CT scan showed that the seventh posterior rib mass disappeared. This case provides valuable information for the potential future treatment of this disease.
Asunto(s)
Janus Quinasa 2 , Síndromes Mielodisplásicos , Sarcoma Mieloide , Humanos , Janus Quinasa 2/genética , Sarcoma Mieloide/patología , Sarcoma Mieloide/genética , Sarcoma Mieloide/tratamiento farmacológico , Sarcoma Mieloide/diagnóstico , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/diagnóstico , Masculino , Mutación , Persona de Mediana Edad , Anciano , Fibrosis , FemeninoRESUMEN
RATIONAL: The Philadelphia chromosome (Ph) is seen in most patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia. However, Ph-positive acute myeloid leukemia (Phâ +â AML) is a rare entity with a poor prognosis and a short median survival period. To date, there have been few clinical reports on this disease. And the treatment regimen of this disease has not been uniformly determined. PATIENT CONCERNS: We report a case of a Phâ +â AML. A 32-year-old male who was admitted to our hospital with weakness for 2 months. DIAGNOSIS: Philadelphia chromosome-positive acute myeloid leukemia. INTERVENTIONS: The patient achieved complete remission by the administration of a tyrosine kinase inhibitor, combined with low-intensity chemotherapy and a B-cell lymphoma 2 inhibitor. Then, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his sister was successfully performed. OUTCOMES: The patient has been in a continuous remission state for 6 months after transplantation. LESSONS: We reported a rare Phâ +â AML case, successfully treated with allo-HSCT. This case provided strong support for treating Phâ +â AML with allo-HSCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Cromosoma Filadelfia , Humanos , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Adulto , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Trasplante Homólogo , Inducción de RemisiónRESUMEN
RATIONALE: Activated phosphoinositide 3-kinase δ syndrome (APDS), a recently described primary immunodeficiency,is caused by autosomal dominant mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta(PIK3CD) gene encoding the p110δ catalytic subunit of PI3Kδ (APDS1) or the PIK3R1 gene that encodes the p85α regulatory subunit of PI3Kδ (APDS2). Gain-of-function mutation of PIK3CD in APDS1 leads to p110δ hyperactivity, with the result of the hyperphosphorylation of downstream mediators of Akt and mammalian target of rapamycin that cause a series of clinical symptoms. Few cases with APDS were reported in Asia. PATIENT CONCERNS: We report a 6-year-old patient with a recurrent respiratory infection, cryptosporidium enteritis, lymphoproliferation, high serum immunoglobulin-M level, anemia, and inverted CD4+/CD8+ ratio. The whole exome sequencing confirmed a heterozygous missense mutation c.3061G>Aï¼p.E1021Kï¼in patient and her mother. Her mutant gene is inherited from her mother, but her mother has not any clinical symptoms. DIAGNOSES: Activated phosphoinositide 3-kinase δ syndrome. INTERVENTIONS: The patient was received immunoglobulin (Ig) replacement therapy, antibiotics, and rapamycin treatment. Through effectively controlling infection and optimal timing of transplantation by adjusting the conditioning regimen, haploidentical Hematopoietic Stem Cell Transplantation(haplo-HSCT) from her brother was successfully performed. OUTCOMES: The patient is in good condiion with a good quality of life after 20 months of follow-up. LESSONS: We reported a rare APDS1 case with PIK3CD E1021K gene mutation, Successfully treated with haplo-HSCT. This case provided a reference for treating APDS with haplo-HSCT.
Asunto(s)
Criptosporidiosis , Cryptosporidium , Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Niño , Femenino , Humanos , Masculino , Fosfatidilinositol 3-Quinasa Clase I/genética , Criptosporidiosis/tratamiento farmacológico , Síndromes de Inmunodeficiencia/genética , Mutación , Fosfatidilinositol 3-Quinasa , Fosfatidilinositol 3-Quinasas/genética , Calidad de Vida , Sirolimus/uso terapéuticoRESUMEN
HLA-A*02:1068Q differs from HLA-A*02:03:01:01 by one nucleotide in exon 1.
Asunto(s)
Antígenos HLA-A , Humanos , Alelos , Pueblos del Este de Asia , Antígenos HLA-A/genética , Nucleótidos , Análisis de Secuencia de ADNRESUMEN
AbstractããLangerhans cell histiocytosis (LCH) is a disease originated from bone marrow dendritic cells, and classified as a tumor by the discovery of a recurrent somatic BRAF-V600E point mutation in the RAS-RAF-MEK-ERK signaling pathway. The clinical manifestations of LCH are mainly granulomatous lesions composed of clonal pathological tissue cells. According to the lesions and invasive risk organs, it is divided into single system diseases, multi-system diseases with risk-free organ infiltration and multi-system diseases with risk organ infiltration. The diagnosis was based on immunohistochemical pathological dendritic cell-specific markers CD1α++and/or CD207+,therefore, according to risk stratification, the regiment and intensity of combination chemotherapy and targeted therapy are drawn up. Prognosis is associates with risk organ infiltration, initial treatment response, and BRAF mutations. Due to the low incidence and lack of systematic knowledge, the clinical understanding of this disease is insufficient, thus the rates of misdiagnosis and therapeutic error are high. In this review, the pathogenesis, clinical manifestations, diagnostic and treatment are summarized. So on to provide a theroretical basis for clinical diagnosis and treatment of the diseases.
Asunto(s)
Histiocitosis de Células de Langerhans , Células Dendríticas , Humanos , Sistema de Señalización de MAP Quinasas , Mutación , Proteínas Proto-Oncogénicas B-raf , Transducción de SeñalRESUMEN
The RhoA effector mDia1 is involved in controlling the balance between filamentous and monomeric actin, but its role in modulating thrombin-induced actin remodeling and platelet spreading on fibrinogen matrices remains unclear. In this study, mDia1 was shown to translocate to the platelet cytoskeleton following thrombin stimulation, in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner. Anti-mDia1 loading or pretreatment with PI 3-kinase inhibitors essentially abrogated thrombin-elicited actin stress fiber formation, with a corresponding decrease in the proportion of platelets exhibiting a fully spread morphology. We also investigated the mechanisms underlying the effects of mDia1 on thrombin-induced actin remodeling and platelet spreading, and found that these involved PI 3-kinase-mediated induction of mDia1 interaction with RhoA. Collectively, these results suggest that the PI 3-kinase/RhoA/mDia1 axis is a critical pathway for coupling thrombin signaling to actin cytoskeletal remodeling during platelet spreading.
Asunto(s)
Actinas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Plaquetas/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Trombina/metabolismo , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Movimiento Celular , Células Cultivadas , Forminas , Humanos , Transporte de Proteínas , Trombina/farmacología , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
OBJECTIVE: To explore the effects of different concentration of pomalidomide on human multiple myeloma cell line MM1.S and the expression of CRBN. METHODS: CCK-8 method was used for detecting inhibition effect of promalidomide on proliferation of MM1.S cells. Apoptosis rate of MM1.S cells was detected by flow cytometry with Annexin V-FITC/PI double staining. Real-time quantitative PCR was used to determine CRBN gene expression level. Western blot was used to detect the effect of pomalidomide on the protein expression of CRBN in MM1.S cells. RESULTS: Pomalidomide has an inhibitory effect on MM1.S cells with time-and dose-dependent manners. Pomalidomide induced apoptosis in MM1.S cells. When the concentration of pomalidomide was 0, 40 and 80 µmol/L, the expression of CRBN gene after the treatment of MM1.S cells for 72 hours was 1.487±0.340, 0.211±0.054 and 0.055±0.005, by using actin as internal refereme. Pomalidomide significantly reduced CRBN protein expression in MM1.S cells. CONCLUSION: Pomalidomide can inhibit the proliferation of MM1.S cells and promote its apoptosis. A certain concentration of pomalidomide can reduce the expression of CRBN gene and down-regulate its protein expression in MM1.S cells.
Asunto(s)
Mieloma Múltiple , Proteínas Adaptadoras Transductoras de Señales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Humanos , Talidomida/análogos & derivados , Ubiquitina-Proteína LigasasRESUMEN
Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and the IDH1 R132H mutation plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating mutant and/or wild-type (WT) IDH1 function remain unknown. Here, we show that two groups of tyrosine kinases (TK) enhance the activation of mutant and WT IDH1 through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or α-ketoglutarate) binding, whereas Y42-phosphorylated dimers show attenuated disruption to monomers. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP+ or NADPH) binding. Diverse oncogenic TKs phosphorylate IDH1 WT at Y42 and activate Src to phosphorylate IDH1 at Y391, which contributes to reductive carboxylation and tumor growth, whereas FLT3 or the FLT3-ITD mutation activates JAK2 to enhance mutant IDH1 activity through phosphorylation of Y391 and Y42, respectively, in AML cells. SIGNIFICANCE: We demonstrated an intrinsic connection between oncogenic TKs and activation of WT and mutant IDH1, which involves distinct TK cascades in related cancers. In particular, these results provide an additional rationale supporting the combination of FLT3 and mutant IDH1 inhibitors as a promising clinical treatment of mutant IDH1-positive AML.See related commentary by Horton and Huntly, p. 699.This article is highlighted in the In This Issue feature, p. 681.
Asunto(s)
Isocitrato Deshidrogenasa/genética , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Línea Celular Tumoral , Manejo de la Enfermedad , Humanos , Isocitrato Deshidrogenasa/química , Janus Quinasa 2/metabolismo , Modelos Biológicos , NADP/metabolismo , Neoplasias/patología , Fosforilación , Unión Proteica , Multimerización de Proteína , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
OBJECTIVE: To investigate the autophagy activity changes of umbilical cord mesenchymal cells (MSC) under hypobaric hypoxia and the effect of hypobaric hypoxia on cell viability. METHODS: Umbilical cord mesenchymal cells were cultured in the chamber of hypobaric hypoxia with an air pressure of 41.1 kPa and an oxygen density of 1%. At 0, 4, 8, 16, 24 and 48 hours, the cells were harvested for Western blot and real-time PCR to observe the expression level of the autophagy marker protein LC3B. And the cell viability under hypobaric hypoxia was evaluated after treatment with autophagy inhibitors HCQ (8 µg/ml) and 3MA (5 mmol/L). RESULTS: LC3B expression in MSC at protein and mRNA levels were up-regulated significantly after being cultured under hypobaric hypoxia condition for 8 hours. And compared with the control group, inhibition of autophagy reduced cell viability while increased Caspase-3 expression and the incidence of apoptosis. CONCLUSION: Hypobaric hypoxia activates autophagy in MSC, and the activation of autophagy might play a protective role for cell survival.
Asunto(s)
Autofagia , Apoptosis , Hipoxia de la Célula , Humanos , Células Madre Mesenquimatosas , Cordón UmbilicalRESUMEN
Cereblonï¼CRBN) is a brain-associated protein with ionic protease activity, which interacts with DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B), and regulator of Cullins 1 (RoC1) to form the functional E3 ubiquitin ligase complex(CRBN-CRL4) that performs proteolysis via the ubiquitin-proteasome pathway. And CRBN is a necessary target protein for the anti-myeloma effect of immunomodulators. The combination of lenalidomide and CRBN recruited a new substrate that binds to the CRBN-CRL4 complex, leading to increased ubiquitination and proteasome-dependent degradation, thus resulting in anti-myeloma activity. The substrates binding to this complex are IKZF1, IKZF3 proteins and GS, etc. The CRBN-dependent degradation of IKZF1 and IKZF3 after lenalidomide treatment is also the result of H2O2-mediated oxidative stress. In addition to ubiquitination, lenalidomide also mediates ubiquitin-independent pathways that prevent CRBN from binding to CD147-MCT1 in a competitive manner to regulate its antitumor activity. Lenalidomide can also play a role in multiple myeloma(MM) cells by modulating miRNA levels and CRBN binding to downstream protein AGO2 expression. Thus, there are many molecular mechanisms of lenalidomide anti-myeloma activity. This review summarizes the molecular mechanisms of CRBN in lenalidomide against myeloma activity in terms of ubiquitin-dependent and ubiquitin-independent pathways.
Asunto(s)
Mieloma Múltiple , Proteínas Adaptadoras Transductoras de Señales , Proteínas Cullin , Humanos , Peróxido de Hidrógeno , Péptido Hidrolasas , Proteolisis , Talidomida , Ubiquitina-Proteína Ligasas , UbiquitinaciónRESUMEN
OBJECTIVE: To evaluate the efficacy of autologous peripheral blood hematopoietic stem cell transplantation (auto-PBHSCT) on patients with multiple myeloma( MM) after Sequential different chemotherapy. METHODS: Seven cases of patients with MM were included in the A group, and 14 cases of patients received 4-6 courses of chemotherapy with VAD and MP before transplantation were included in the B group and received 4-6 courses of chemotherapy with VTD and VD before transplantation. Auto-peripheral blood hematopoietic stem cell were mobilized by G-CSF. Condition regimen were melphalan(A group) or bortezomib combined melphalan(B group). IFN-α(A group) or Thalidomide(B group) was used as maintenance treatment after auto-PBHSCT. RESULTS: Two cases of patients reached to complete remission (CR)(2/7,28.6%),1 case got very good partial remission (VGPR) (1/7,14.3%), 4 cases got partial remission(PR) (4/7,57.1%) in A group, and 9 cases got CR (9/14,64.3%), 3 cases got VGPR(3/14,21.4%), and 2 cases got PR(2/14,14.3%) in the B group before auto-PBHSCT. The CR and VGPR were significant difference between 2 groups (P<0.05). All the patients got hematopoietic recovery. In 2 groups, the median time of ANC recovery≥0.5×109/L was 13 (11-16) and 14ï¼11-18ï¼days, that of WBC recovery ≥4.0×109/L were 16(15-19) and 18(16-20)days, Plt recovery ≥ 50 ×109/L was 21 (18-25) and 21(17-25) days. Bone marrow showed CR in 21 to 28 days after transplantation. All of 7 cases of patients remised in 6 to 47 months after transplantation, and 4 cases died lastly and 3 cases failed to be followed up in A group. The median time of progression-free survival(PFS) was 36(6-47) months, and that of overall survival(OS) was 37(7-50) months. In B group, 2 cases of patients remissed in 5 and 17 months after transplantation, and did lastly, 1 case relieved in 12 months after transplantation and failed to be followed up. 1 case of patient relived in 46 months after transplantation, and then received the second auto-PBHSCT, and got CR for 105 months. Other 10 cases got CR, their median time of PFS was 45.5(4-105) months, the median time of overall survival(OS) was 45.5(4-105) months. The PFS and OS were very significant different between 2 groups (P<0.01). CONCLUSION: Bortezomib-based chemotherapy, Auto-PBHSCT and maintenance treatment with thalidomide were favorable to the patients of MM for survival prolongation.
Asunto(s)
Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Trasplante de Células Madre Hematopoyéticas , Humanos , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica , Trasplante Autólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore the characteristics of cytogenetics and molecular genetics in patients with multiple myeloma(MM). METHODS: Fluorescence in situ hybridization(FISH) was used for molecular genetics analysis in 86 cases of newly diagnosed MM, at the same time the chromosome karyotype analysis was performed in 20 cases. Specimen were bone marrow cells. RESULTS: FISH detection showed that 68 cases of MM (79.07%) had at least one type of the molecular genetic abnormalities. The positive rates of IgH rearrangement, 1q21 amplification, D13S319 deletion, RB1 deletion and.P53 deletion were 62.79%, 26.74%, 24.42% ,13.95% and 1.16%, respectively. The positive rate of IgH was significantly higher than that of any other probes(P<0.01). The positive rate of IgH was 79.41% in 68 cases. Out of which the positive rate of IgH single and combined with 1, 2, 3, 4 probes was 59.26%, 24.07%, 11.11%, 5.56% and 0 respectively. The positive rate of IgH only was very signficantly higher than that of combined with any other probes(P<0.01).The positive rate of 1q21 was 33.82% in 68 cases, Out of which the positive rates of 1q21 or combined with 1,2,3,4 probes was 21.74%, 43.48%, 21.74%,13.04% and 0 respectively, the 1q21 probe showed positive as combined with other probes(P<0.01), especially with IgH(P<0.05). The positive rates of D13S319 were 30.88% in 68 cases of patients, out of which the positive rates of D13S319 single or combined with 1, 2, 3, 4 probes was 14.29%, 28.57%, 42.86%, 14.29% and 0 respectively, the D13S319 combined with other probes appeared more significant positive(P<0.01), especially with 1 or 2 probes (P< 0.01). The positive rate of RB1 was 17.65% in 68 cases, the positive rate of RB1 singl or combined with 1, 2, 3, 4 probes were 0, 25%, 50%, 25% and 0, the RB1 appeared positive always combined with other probes, especially with D13S319 probe (P<0.01). The positive rate of P53 was 1.47%, as combined with RB1 and D13S319 probes. The chromosomal karyotyping showed that 3 cases carried abnormal chromosomal and 17 cases carried normal chromosome, Out of which 17 cases showed positive by FISH. There was a significant difference of sensitivity between FISH combined with chromosome karvotyping and single chromosome karvotype (P< 0.01). CONCLUSION: The genetic abnormalies display obvious heterogenicity in MM. The sensitivity of FISH is higher than that of chromosomal karvotyping. If FISH and chromosome karvotyping are combined, the positive rate of abnormality can be raised.
Asunto(s)
Mieloma Múltiple , Aberraciones Cromosómicas , Cromosomas Humanos Par 13 , Humanos , Hibridación Fluorescente in Situ , Mieloma Múltiple/genética , Estudios RetrospectivosRESUMEN
OBJECTIVE: To explore the correlation between JAK/STAT signaling pathways and pathogenesis of immune thrombocytopenia(ITP). METHODS: Twenty-six newly-diagnosed ITP patients was included in this study. They all meet the clinical and hematological criteria for the diagnosis of ITP, and patients with coronary heart disease, severe refractory hypertension, diabetes or with severe liver or kidney function incompetence were ruled out. 24 healthy control without autoimmune diseases, viral infectious diseases and with normal liver and kidney functions were also included. The expressions of Jak3, p-Jak3 mRNA, Stat3, and p-Stat3 were tested and the changes in levels of IL-21 mRNA, IL-21 cell secretion after DEX intervention and AG490 blockade were measured. RESULTS: Compared with the healthy control, patients with ITP had significantly high expressions of Jak3, p-Jak3 mRNA, Stat3 and p-Stat3 protein, which significantly reduced after AG490 blocking (P<0.01). The expression of IL-21 mRNA and the secretion of IL-21 obviously decreased after DEX intervention, but increased after AG490 blocking(P<0.01). CONCLUSION: The pathogenesis of ITP associates with the activation of JAK/STAT signaling pathways, and IL-21-mediated JAK/STAT signaling pathways play regulatory role in ITP.
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Púrpura Trombocitopénica Idiopática , Humanos , Interleucinas , Factor de Transcripción STAT3 , Transducción de SeñalRESUMEN
Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized "precision diets" that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile.
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Grasas de la Dieta/efectos adversos , Cuerpos Cetónicos/metabolismo , Melanoma/patología , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Ácido 3-Hidroxibutírico/farmacología , Acetoacetatos/administración & dosificación , Acetoacetatos/sangre , Acetoacetatos/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Hipolipemiantes/farmacología , Inyecciones Intraperitoneales , Melanoma/sangre , Ratones , Ratones Desnudos , Pironas/química , Pironas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To investigate the correlation between the HLA genes and pathogenesis of aplastic anemia (AA), so as to find the susceptible AA genes. METHODS: Polymerase chain reaction with specific sequence primers (PCR-SSP) method was used to detect the HLA typing of 50 AA patients and 183 normal healthy individuals as controls in Chinese Han population of northwestern plateau. RESULTS: The frequency of HLA-A* 0201 (45.0%), B* 1501 (11.0%), B* 5501 (9.0%) and DRB1* 0901 (19.0%) gene frequences in AA patients were significantly higher than those in controls (Odds Ratio: OR=1.657, 2.138, 2.314 and 1.932, x2=4.882, 3.876, 3.863 and 4.473 (P<0.05). In contrast, A* 0301 gene frequency (4.0%) in AA was significantly lower than that in controls, OR=0.349, x2=4.154 (P<0.05). The male HLA-A* 0201 gene frequency was lower than that in female (38.2% vs 59.4%), and the difference was statistically significant (P<0.05). Concludsion: The HLA-A* 0201, B* 1501, B* 5501 and DRB1* 0901 genes may be considered as the risk markers while A* 0301 gene as a protective marker of AA, the HLA-A* 0201 also shows the sex differences.
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Anemia Aplásica/genética , Cadenas HLA-DRB1/genética , Polimorfismo Genético , Alelos , Pueblo Asiatico/genética , China , Femenino , Frecuencia de los Genes , Humanos , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: To investigate the efficacy of autologous peripheral blood hematopoietic stem cell transplantation(auto-PBHSCT) combined with adoptive immunotherapy for patients with B lymphocyte malignant lymphoma(ML). METHODS: A total of 110 cases of ML treated with adoptive immunotherapy after auto-PBHSCT from January 2000 to December 2009 were enrolled in adoptive immunotherapy group (treated group), while 74 cases of ML treated without adoptive immunotherapy after auto-PBHSCT from January 1995 to December 1999 were used as control group. The efficacy of 2 groups were analyzed and compared, 110 case of ML in treated group included 78 cases of non-Hodgkin's lymphoma(NHL), 32 cases of Hodgkin's lymphoma(HL),74 cases of ML in control group included 52 NHL and 22 HL. All of the patients were treated sequentially with chemotherapy regimens for 6 courses. After that, all the patients received auto-PBHSCT. After hematopoietic reconstruction, the patients in treated group were given 6 courses of adoptive immunotherapy(rhIL-2 100 WU/day for 10 days monthly for each course), while the patients in control group were not given immunotherapy. All the patients were followed-up for more than 5 years. RESULTS: There was one patient in each group, who died of liver failure and cerebral hemorrhage respectively within 3 and 2 months, and all the other patients achieved hematopoietic reconstruction. Following-up for 1, 3, 5 years, the disease-free survival (DFS) rate in treated group was 97.3%,93.6%,87.3% while 91.9%, 73.0%, 64.9% in control group. Following-up for 3 and 5 years, there was very significant difference in DFS between 2 groups(P<0.01). The 1,3 and 5 year DFS rate of patients in stage I/II and III/IV in the treated group were 100%,100%,91.7% and 96.5%,91.9%,86.0% respectively while DFS of control group was 100%, 93.3%, 86.7% and 89.8%, 67.8%, 59.3%, there was a significant difference in 3 and 5 years DFS of III/IV stage patients between 2 groups (P<0.01). The 1,3 and 5 year DFS rate of HL patients were 100%, 93.8%,84.4% in treated group and 100%,72.7%,59.1% in control group respectively. There was significant difference in 3 and 5 years DFS of HL between 2 groups (P<0.05). The 1,3 and 5 year DFS rate of stage I/II HL patients were 100%,100%,88.9% in treated group and 100%,100%,80.0% in control group. The 1,3 and 5 year DFS of HL patients in stage III/IV was 100%,91.3%,82.6% and 94.1%,64.7%,52.9% respectively. There was significant difference in 3 and 5 years DFS of III/IV stage of HL patients between 2 groups (P<0.05). The 1,3 and 5 year DFS rate of NHL patients is 96.2%, 93.6%,88.5% in treated group and 90.4%,73.1%,65.4% in control group respectively. There was a significant difference in 3 and 5 years DFS of NHL between 2 groups(P<0.01). The 1,3 and 5 year DFS rate of stage I/II NHL patients was 100%, 100%, 93.3.9% in treated group and 100%, 90%, 90.0% in control group, respectively. The 1,3 and 5 year DFS of NHL patients in stage III/IV is 95.2%, 92.1%,87.3% and 88.1%,69.0%, 59.5% respectively. There was significant difference in 3 and 5 years DFS of III/IV stage NHL patients between 2 groups (P<0.05). CONCLUSION: Therapeutic efficacy is satisfactory for the patients of B lymphocyte ML treated with adoptive immunotherapy after auto-PBHSCT, especially benefited the patients of stage III/IV significantly.