RESUMEN
Researchers in the field of acute myeloid leukemia have long sought to establish a prognostic stratification system for clinical use that combines multiple genetic mutations. In 2022, the European LeukemiaNet (ELN) proposed a new prognostic model incorporating new genetic mutations. However, Japanese National Health insurance only recently began covering clinical genetic analysis for AML. We established the Multi-center Collaborative Program for Gene Sequencing of Japanese AML (GS-JAML) to contribute to clinical practice by providing rapid genetic analysis results. Retrospective analysis of this research program revealed (1) the clinical significance of CEBPA-bZIP mutations, and (2) the clinical significance of DNMT3A mutations in NPM1 mutated AML.
Asunto(s)
Leucemia Mieloide Aguda , Mutación , Nucleofosmina , Guías de Práctica Clínica como Asunto , Humanos , Leucemia Mieloide Aguda/genética , Pueblo Asiatico/genética , Pruebas Genéticas , Femenino , Masculino , Pronóstico , Pueblos del Este de AsiaRESUMEN
Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage-induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment of the AKT/mTORC1 pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.
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Apoptosis , Caspasa 2 , Proliferación Celular , Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Caspasa 2/metabolismo , Caspasa 2/genética , Humanos , Animales , Diferenciación Celular , Línea Celular Tumoral , Autorrenovación de las Células/genética , Ratones , Daño del ADNRESUMEN
Nucleophosmin (NPM1) is a key nucleolar protein released from the nucleolus in response to stress stimuli. NPM1 functions as a stress regulator with nucleic acid and protein chaperone activities, rapidly shuttling between the nucleus and cytoplasm. NPM1 is ubiquitously expressed in tissues and can be found in the nucleolus, nucleoplasm, cytoplasm, and extracellular environment. It plays a central role in various biological processes such as ribosome biogenesis, cell cycle regulation, cell proliferation, DNA damage repair, and apoptosis. In addition, it is highly expressed in cancer cells and solid tumors, and its mutation is a major cause of acute myeloid leukemia (AML). This review focuses on NPM1's structural features, functional diversity, subcellular distribution, and role in stress modulation.
Asunto(s)
Nucléolo Celular , Proteínas Nucleares , Nucleofosmina , Estrés Fisiológico , Humanos , Proteínas Nucleares/metabolismo , Nucléolo Celular/metabolismo , Animales , Fosfoproteínas/metabolismoRESUMEN
Next-generation sequencing of samples from patients with acute myeloid leukemia (AML) has revealed several driver gene mutations in adult AML. However, unlike other cancers, AML is defined by relatively few mutations per patient, with a median of 4-5 depending on subtype. In this review, we will discuss the most common driver genes found in patients with AML and focus on the most clinically relevant ones that impact treatment strategies. The most common driver gene mutations in AML occur in NPM1 and FLT3, accounting for ~30% each. There are now targeted therapies being tested or already approved for these driver genes. Menin inhibitors, a novel targeted therapy that blocks the function of the menin protein, are in clinical trials for NPM1 driver gene mutant AML after relapse. A number of FLT3 inhibitors are now approved for FLT3 driver gene mutant AML in combination with chemotherapy in the frontline and also as single agent in relapse. Although mutations in IDH1/2 and TP53 only occur in around 10-20% of patients with AML each, they can affect the treatment strategy due to their association with prognosis and availability of targeted agents. While the impact of other driver gene mutations in AML is recognized, there is a lack of data on the actionable impact of those mutations.
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Leucemia Mieloide Aguda , Mutación , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación/genética , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/metabolismo , Terapia Molecular DirigidaRESUMEN
BACKGROUND: Nucleophosmin 1 (NPM1) gene-mutated acute myeloid leukemia (NPM1mut AML) is classified as a subtype with a favorable prognosis. However, some patients fail to achieve a complete remission or relapse after intensified chemotherapy. Genetic abnormalities in concomitant mutations contribute to heterogeneous prognosis of NPM1mut AML patients. METHODS: In this study, 91 NPM1-mutated and FLT3-ITD wild-type (NPM1mut/FLT3-ITDwt) AML patients with intermediate-risk karyotype were enrolled to analyze the impact of common genetic co-mutations on chemotherapeutic outcome. RESULTS: Our data revealed that TET1/2 (52/91, 57.1%) was the most prevalent co-mutation in NPM1mut AML patients, followed by IDH1/2 (36/91, 39.6%), DNMT3A (35/91, 38.5%), myelodysplastic syndrome related genes (MDS-related genes) (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 genes) (35/91, 38.5%), FLT3-TKD (27/91, 29.7%) and GATA2 (13/91, 14.3%) mutations. Patients with TET1/2mut exhibited significantly worse relapse-free survival (RFS) (median, 28.7 vs. not reached (NR) months; p = 0.0382) compared to patients with TET1/2wt, while no significant difference was observed in overall survival (OS) (median, NR vs. NR; p = 0.3035). GATA2mut subtype was associated with inferior OS (median, 28 vs. NR months; p < 0.0010) and RFS (median, 24 vs. NR months; p = 0.0224) compared to GATA2wt. By multivariate analysis, GATA2mut and MDS-related genesmut were independently associated with worse survival. CONCLUSION: Mutations in TET1/2, GATA2 and MDS-related genes were found to significantly influence the chemotherapeutic outcome of patients with NPM1mut AML. The findings of our study have significant clinical implications for identifying patients who have an adverse response to frontline chemotherapy and provide a novel reference for further prognostic stratification of NPM1mut/FLT3-ITDwt AML patients.
Asunto(s)
Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Tirosina Quinasa 3 Similar a fms , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Adulto , Tirosina Quinasa 3 Similar a fms/genética , Anciano , Pronóstico , Adulto Joven , Resultado del Tratamiento , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.
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Colitis , Inmunidad Mucosa , Ratones Noqueados , Mitocondrias , Proteínas Nucleares , Nucleofosmina , Fosforilación Oxidativa , Animales , Mitocondrias/metabolismo , Ratones , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Humanos , Colitis/inmunología , Colitis/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Interleucina-22 , Inmunidad Innata , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Sulfato de Dextran , Masculino , Interleucinas/metabolismo , Interleucinas/genética , Interleucinas/inmunología , FemeninoRESUMEN
OBJECTIVE: To investigate the clinical characteristics and influence of co-mutated gene on acute myeloid leukemia patients (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. METHODS: A total of 273 FLT3+ AML patients were enrolled, and the co-mutation gene data of the patients were collected to further analyze the prognosis of the patients. FLT3 and other common mutations were quantified by PCR amplification products direct sequencing and second-generation sequencing (NGS). RESULTS: When patients were divided into FLT3- ITD +, FLT3- TKD +, FLT3- ITD ++TKD + and FLT3- ITD -+TKD - group according to the type of FLT3 mutations, it was found that the frequencies of TET2, GATA2, NRAS and ASXL1 mutation were significantly different among the 4 groups (all P < 0.05). When patients were divided into allelic ratio (AR) ≥0.5 and <0.5 group, it was found that the frequencies of FLT3- ITD +, FLT3 -ITD - +TKD -, NPM1, NRAS and C-kit were significantly different between the two groups (all P < 0.05). When patients were divided into normal and abnormal karyotype group, it was found that the frequencies of FLT3- ITD +, FLT3- TKD +, NPM1, GATA2 and C-kit were significantly different between the two groups (all P < 0.05). The median overall survival (OS) of AML patients with FLT3 -TKD + (including FLT3- ITD ++TKD +) was longer than that of patients with FLT3- ITD + alone (P < 0.05). The OS and relapse-free survival (RFS) of AML patients with FLT3++TET2+ were both shorter than those of patients with FLT3++TET2- (both P < 0.05). CONCLUSION: The mutation frequencies of co-mutated genes are correlated with subtypes of FLT3, karyotype and AR. AML patients with FLT3 -TKD + have longer OS than patients with FLT3- ITD + alone, and patients with co-mutation of TET2 have shorter median OS and RFS.
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Dioxigenasas , GTP Fosfohidrolasas , Leucemia Mieloide Aguda , Mutación , Nucleofosmina , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/genética , Pronóstico , GTP Fosfohidrolasas/genética , Proteínas de Unión al ADN/genética , Factor de Transcripción GATA2/genética , Proteínas Represoras/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-kit/genéticaRESUMEN
OBJECTIVE: To investigate the incidence of PTPN11 gene mutation and its associated gene mutations in adult patients with acute myeloid leukemia (AML), and analyze its clinical characteristics. METHODS: Second-generation sequencing and Sanger sequencing were used to detect 51 gene mutations, and multiplex-PCR was used to detect 41 fusion genes from 451 newly diagnosed adult AML patients admitted to Affiliated Hospital of Jiangnan University, Changzhou Second People's Hospital, Wuxi People's Hospital and Wuxi Second People's Hospital from January 2017 to July 2022. RESULTS: Among 451 primary adult AML patients, the PTPN11 gene mutation was detected in 34 cases, and the mutation rate was 7.5%. In the 34 patients, 37 PTPN11 alterations were found, which were exclusively missense mutations affecting residues located within the N-SH2 (31 cases) and PTP (6 cases) domains and clustered overwhelmingly in exon 3. The platelet count of PTPN11 mutation patients was 76.5(23.5, 119.0)×109/L, which was significantly higher than 41.0(22.0, 82.5)×109/L of wild-type patients (P < 0.05). While, there were no significant differences in sex, age, peripheral white blood cell count, hemoglobin, and bone marrow blast between PTPN11 mutation and wild-type patients (P >0.05). In FAB subtypes, PTPN11 mutations were mainly distributed in M5, followed by M2 and M4, less frequently in M3 and M6. There was no significant difference in the distribution of FAB subtypes between PTPN11 mutation and wild-type patients (P >0.05). A total of 118 AML patients were detected positive fusion gene, among which patients with PTPN11 mutations had a higher incidence of positive MLL-AF6 than wild-type ones (P < 0.01). 97.1% of 34 patients with PTPN11 mutations were accompanied by other mutations, in descending order, they were respectively NPM1 (38.2%), NRAS (32.4%), FLT3-ITD (32.4%), DNMT3A (32.4%) and KRAS (23.5%), etc . CONCLUSION: PTPN11 mutation has a certain incidence in AML patients and is clustered overwhelmingly in exon 3. ALL of them are exclusively missense mutations, and most often present in conjunction with NPM1 mutations. FAB typing of PTPN11 mutation is mostly manifested as M5 subtype, which is associated with higher platelet counts.
Asunto(s)
Leucemia Mieloide Aguda , Mutación , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Humanos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Leucemia Mieloide Aguda/genética , Adulto , Nucleofosmina , Exones , Masculino , FemeninoRESUMEN
Pyroptosis of programmed cell death has been recognized as a more effective way to inhibit the occurrence and development of tumors than the better-studied apoptosis. However, it is still challenging to quickly and effectively trigger pyroptosis of cancer cells for high-efficacy cancer treatment. Here, we report on the first use of mild constant-potential electrostimulation (cp-ES) to quickly trigger cancer cell pyroptosis with a probability up to â¼91.4% and significantly shortened time (within 1 h), â¼3-6 times faster than typical drug stimulation to induce pyroptosis. We find that the ES-induced cancer cell pyroptosis is through the activated caspase-3 (pathway) cleavage of gasdermin E (GSDME) to form an N-terminal fragment (GSDME-N) and observe nuclear shrinkage and reduction of the number of nucleoli as well as down-/up-regulated expression of two important nucleoproteins of nucleolin and nucleophosmin (NPM1). The study enriches the basic understanding of pyroptosis and provides a new avenue for potential effective treatment of cancer.
Asunto(s)
Caspasa 3 , Nucleofosmina , Piroptosis , Humanos , Caspasa 3/metabolismo , Nucleolina , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión al ARN/metabolismo , GasderminasRESUMEN
Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients' group with more than 30 G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.
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Leucemia Mieloide Aguda , Nucleofosmina , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Pronóstico , Femenino , Masculino , Fosforilación , Persona de Mediana Edad , Anciano , Adulto , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Biomarcadores de Tumor/metabolismo , Anciano de 80 o más Años , Fosfoproteínas Fosfatasas/metabolismo , Fosfoproteínas Fosfatasas/genética , Adulto Joven , Tasa de Supervivencia , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Adolescente , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas NuclearesAsunto(s)
Leucemia Mieloide Aguda , Gammopatía Monoclonal de Relevancia Indeterminada , Mutación , Proteínas Nucleares , Nucleofosmina , Células Plasmáticas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Proteínas Nucleares/genética , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Células Plasmáticas/patología , Células Plasmáticas/metabolismo , Masculino , Cuerpos de Inclusión/patología , Femenino , Persona de Mediana EdadRESUMEN
Quantitative assessment of nucleophosmin 1 (NPM1) mutation status is integral to evaluating measurable residual disease (MRD) in NPM1-mutated acute myeloid leukemia (AML) patients. In a retrospective study, leftover peripheral blood (PB) specimens (n = 40) which were collected for routine clinical diagnostic evaluations of AML disease burden were tested by both a novel automated RT-qPCR quantitative NPM1 assay (Xpert NPM1 mutation assay) and the NPM1 mutA, mutB&D MutaQuant kit. Based on a Deming regression analysis, there was a high correlation (slope = 0.92; intercept = 0.12; Pearson's r = 0.982) between the quantitative results of the Xpert NPM1 mutation assay and the NPM1 mutA, mutB&D MutaQuant kit. The Xpert test quantitative results are thus highly correlated with the comparator method and the former has potential as a useful alternative for the monitoring of AML patients with a known NPM1 mutation.
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Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Reacción en Cadena en Tiempo Real de la Polimerasa , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Proteínas Nucleares/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Estudios Retrospectivos , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Masculino , Femenino , Persona de Mediana EdadRESUMEN
Previous prospective randomized trials have investigated the efficacy of gemtuzumab ozogamicin in the frontline treatment of acute myeloid leukemia (AML). We evaluated the efficacy of high-dose cytarabine with GO as consolidation therapy in 20 patients with favorable- or intermediate-risk AML in first complete remission. They included six patients with wild-type nucleophosmin (NPM1) core binding factor (CBF), ten with NPM1-mutated non-CBF, and four with wild-type NPM1 non-CBF. The median follow-up for the entire cohort was 62.0 months. The three-year overall survival (OS) and relapse-free survival (RFS) rates were 72.2% and 77.8%, respectively. OS and RFS were significantly higher for NPM1-mutated non-CBF AML than for wild-type NPM1 non-CBF AML (p = 0.001). We also examined the CD33 single-nucleotide polymorphism (SNP) rs12459419, which has been reported to influence the therapeutic efficacy of GO and CD33 expression. The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.
Asunto(s)
Aminoglicósidos , Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Consolidación , Citarabina , Gemtuzumab , Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Gemtuzumab/administración & dosificación , Citarabina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Femenino , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Aminoglicósidos/administración & dosificación , Adulto , Polimorfismo de Nucleótido Simple , Lectina 3 Similar a Ig de Unión al Ácido Siálico/genética , Proteínas Nucleares/genética , Mutación , Resultado del TratamientoRESUMEN
Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.
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Adenocarcinoma del Pulmón , Resistencia a Antineoplásicos , Receptores ErbB , Glutatión Transferasa , Neoplasias Pulmonares , Proteínas Nucleares , Nucleofosmina , Inhibidores de Proteínas Quinasas , Humanos , Resistencia a Antineoplásicos/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Ratones , Línea Celular Tumoral , Metástasis de la Neoplasia , Transducción de Señal , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , FN-kappa B/metabolismoAsunto(s)
Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Proteínas Nucleares/genética , Pronóstico , Femenino , Masculino , Adulto , Persona de Mediana Edad , Anciano , Adulto Joven , Anciano de 80 o más AñosRESUMEN
Pure erythroid leukemia (PEL) is an extremely rare subtype of acute myeloid leukemia (AML). Although not specific, PEL is almost uniformly associated with complex karyotype and TP53 mutations. Given the rarity of the disease, our understanding of its cytogenetic and molecular features deems incomplete. We aim to complement existing literature by presenting an unusual case of PEL. The case is comprehensively worked up with multiple modalities. We present for the first time a case of PEL with unusual cytogenetic and molecular features: normal karyotype with absence of TP53 mutations and presence of NPM1 and NRAS mutations. This is a valuable addition to literature, expanding our understanding of molecular and cytogenetic spectra of PEL.
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Leucemia Eritroblástica Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Humanos , Proteínas Nucleares/genética , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/patología , Cariotipo , Masculino , Proteína p53 Supresora de Tumor/genética , Femenino , Persona de Mediana EdadRESUMEN
HOXA9, an important transcription factor (TF) in hematopoiesis, is aberrantly expressed in numerous cases of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is a strong indicator of poor prognosis in patients. HOXA9 is a proto-oncogene which is both sufficient and necessary for leukemia transformation. HOXA9 expression in leukemia correlates with patient survival outcomes and response to therapy. Chromosomal transformations (such as NUP98-HOXA9), mutations, epigenetic dysregulation (e.g., MLL- MENIN -LEDGF complex or DOT1L/KMT4), transcription factors (such as USF1/USF2), and noncoding RNA (such as HOTTIP and HOTAIR) regulate HOXA9 mRNA and protein during leukemia. HOXA9 regulates survival, self-renewal, and progenitor cell cycle through several of its downstream target TFs including LMO2, antiapoptotic BCL2, SOX4, and receptor tyrosine kinase FLT3 and STAT5. This dynamic and multilayered HOXA9 regulome provides new therapeutic opportunities, including inhibitors targeting DOT1L/KMT4, MENIN, NPM1, and ENL proteins. Recent findings also suggest that HOXA9 maintains leukemia by actively repressing myeloid differentiation genes. This chapter summarizes the recent advances understanding biochemical mechanisms underlying HOXA9-mediated leukemogenesis, the clinical significance of its abnormal expression, and pharmacological approaches to treat HOXA9-driven leukemia.
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Regulación Leucémica de la Expresión Génica , Proteínas de Homeodominio , Nucleofosmina , Proto-Oncogenes Mas , Humanos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Animales , Leucemia/genética , Leucemia/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) can be monitored by quantitative PCR after having achieved first complete remission (CR) to detect morphologic relapse and drive preemptive therapy. How to best manage these patients is unknown. We retrospectively analyzed 303 patients with CBF and NPM1-mutated AML, aged 18-60 years, without allogeneic hematopoietic cell transplantation (HCT) in first CR, with molecular monitoring after first-line intensive therapy. Among these patients, 153 (51%) never relapsed, 95 (31%) had molecular relapse (53 received preemptive therapy and 42 progressed to morphologic relapse at salvage therapy), and 55 (18%) had upfront morphologic relapse. Patients who received preemptive therapy had higher OS than those who received salvage therapy after having progressed from molecular to morphologic relapse and those with upfront morphologic relapse (three-year OS: 78% vs. 51% vs. 51%, respectively, P = 0.01). Preemptive therapy included upfront allogeneic HCT (n = 19), intensive chemotherapy (n = 21), and non-intensive therapy (n = 13; three-year OS: 92% vs. 79% vs. 58%, respectively, P = 0.09). Although not definitive due to the non-randomized allocation of patients to different treatment strategies at relapse, our study suggests that molecular monitoring should be considered during follow-up to start preemptive therapy before overt morphologic relapse.
Asunto(s)
Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Adulto , Persona de Mediana Edad , Femenino , Masculino , Proteínas Nucleares/genética , Adolescente , Adulto Joven , Estudios Retrospectivos , Recurrencia , Trasplante de Células Madre Hematopoyéticas/métodos , Factores de Unión al Sitio Principal/genética , Pronóstico , Terapia Recuperativa , Inducción de Remisión , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patologíaRESUMEN
Aldehyde dehydrogenases superfamily (ALDHs), which are ubiquitously present in various organisms with diverse subcellular localizations, play a crucial role in regulating malignant tumor progression; Nevertheless, their involvement in clear cell renal cell carcinoma (ccRCC) has not been elucidated. In this study, we performed comprehensive bioinformatics analyses on the 19 ALDHs genes, and identified ALDH9A1 as a key contributor in ccRCC. Expression patterns and clinical relevance of ALDH9A1 were determined using bioinformatics analyses, real-time PCR, western blotting, and immunohistochemistry. To explore the underlying mechanism behind the tumor suppressor role of ALDH9A1, RNA sequencing, methylated RNA immunoprecipitation, luciferase reporter assay, mass spectroscopy, immunoprecipitation, mutational studies and immunofluorescence were employed. The impact of ALDH9A1 in ccRCC progression and metabolic programming was assessed through both in vitro and in vivo. Here, this study revealed ALDH9A1 as a tumor suppressor gene in ccRCC. The fat mass and obesity associated protein (FTO) was identified as a demethylase for ALDH9A1 mRNA, resulting in its reduced stability and expression levels in ccRCC. Functional experiments demonstrated that the deficiency of ALDH9A1 in ccRCC promoted tumor proliferation, invasion, migration and lipid accumulation. Mechanistic insights illustrated that the diminished levels of ALDH9A1 resulted in the failure to sequester nucleophosmin 1 (NPM1) within cytoplasm, thereby suppressing the transcription of IQ motif containing the GTPase-activating protein 2 (IQGAP2), subsequently activating the AKT-mTOR signaling, ultimately fostering tumor progression and lipid accumulation. In conclusion, the present study highlights the robust prognostic significance of ALDH9A1 and delivers a comprehensive understanding of ALDH9A1-NPM1-IQGAP2-AKT axis in ccRCC. These findings established a solid research foundation for novel therapeutic strategies for ccRCC patients.