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1.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652823

RESUMEN

Fluorescence in situ hybridization (FISH) and Hi-C methods are largely used to investigate the three-dimensional organization of the genome in the cell nucleus and are applied here to study the organization of genes (LMBR1, NOM1, MNX1, UBE3C, PTPRN2) localized in the human 7q36.3 band. This region contains the MNX1 gene, which is normally not expressed in human lymphocytes beyond embryonic development. However, this homeobox gene is frequently activated in leukemic cells and its expression is associated with an altered gene positioning in the leukemia cell nuclei. In this study, we used FISH on 3D-preserved nuclei to investigate the nuclear positioning of MNX1 in the leukemia-derived cell line K562. Of the five copies of the MNX1 gene present in K562, four alleles were positioned in the nuclear periphery and only one in the nuclear interior. Using the Juicebox's Hi-C dataset, we identified five chromatin loops in the 7q36.3 band, with different extensions related to the size and orientation of the genes located here, and independent from their expression levels. We identified similar loops in 11 human and three mouse cell lines, showing that these loops are highly conserved in different human cell lines and during evolution. Moreover, the chromatin loop organization is well conserved also during neuronal cell differentiation, showing consistency in genomic organization of this region in development. In this report, we show that FISH and Hi-C are two different approaches that complement one another and together give complete information on the nuclear organization of specific chromosomal regions in different conditions, including cellular differentiation and genetic diseases.


Asunto(s)
Cromatina/genética , Cromosomas Humanos/genética , Proteínas de Homeodominio/genética , Leucemia/genética , Familia de Multigenes , Factores de Transcripción/genética , Animales , Línea Celular Tumoral , Núcleo Celular/genética , Humanos , Hibridación Fluorescente in Situ , Ratones
2.
Mol Biol (Mosk) ; 55(1): 139-151, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33566033

RESUMEN

Dysfunction of genes that control mitosis and are responsible for the correct segregation of sister chromatids in anaphase is often accompanied by aneuploidy, which is frequently detected in leukemia. One of the components of the kinetochore complex, namely, the AF15q14/KNL1/CASC5 protein, is an important factor ensuring the correct binding of the pericentromeric region of chromosomes with the spindle microtubules. As shown recently, in some leukemias, the gene of this protein can be involved in the generation of the chromosomal translocation t(11;15)(q23;q14) or a variant of the chimeric MLL-AF15Q14 oncogene, which serves as a biomarker of poor prognosis. Despite the implication of mRNA of the CASC5 gene in oncogenesis of solid tumors, expression of this gene in hematopoietic neoplasms has not been studied. We analyzed expression levels of the CASC5 gene and the nearest regulatory genes, including WT1, APOBEC3A (A3A), and N-MYC. A pronounced decrease in CASC5 expression in bone marrow cells of primary leukemia patients compared with healthy donors was found. It was also shown that reduced expression of the CASC5 gene correlates with the detection of targeted mutations in patients composed two prognostic subgroups (favorable, unfavorable) with a significance level (p <0.05). It was noted that the change in the expression level of the CASC5 gene in acute myeloid leukemia is associated with overexpression of the genes WT1, A3A, and in some cases N-MYC and SPT16, which is consistent with the resistance to chemotherapy and leukemia progression. However, the question of which regulatory gene initiates leukemogenesis remains open.


Asunto(s)
Leucemia Mieloide Aguda , Leucemia , Proteínas de Ciclo Celular/genética , Citidina Desaminasa , Expresión Génica , Humanos , Leucemia/genética , Proteínas Asociadas a Microtúbulos/genética , Proteína de la Leucemia Mieloide-Linfoide , Proteínas , Translocación Genética
3.
Exp Hematol ; 94: 31-36, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33453340

RESUMEN

BAALC is identified as a leukemia-associated gene and is highly expressed in CD34-positive hematopoietic stem cells. High BAALC expression is associated with poor prognosis in several types of acute myeloid leukemia. We explored binding partner proteins of BAALC by means of mass spectrometry and analyzed biological properties of BAALC-expressing leukemic cells. We found that BAALC physically interacts with DBN1, which is an actin-binding protein and promotes cell adhesion and mobility by forming cell membrane spines during cell-cell interactions. Drebrin1 downregulation impeded cell adhesion to bone marrow stromal cells, resulting in improvement of sensitivity to cytarabine. Taken together, our findings suggest that BAALC-DBN1 interaction contributes to the anchoring of BAALC-expressing cells in the bone marrow, which in turn leads to resistance to cytotoxic drugs. Therefore, the BAALC-DBN1 interaction provides us with an opportunity to overcome the chemotherapy resistance in BAALC-activated leukemia via functional blockage of these genes.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Citarabina/farmacología , Resistencia a Antineoplásicos , Leucemia/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Neuropéptidos/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Células Jurkat , Leucemia/genética , Leucemia/metabolismo , Proteínas de Neoplasias/genética , Neuropéptidos/genética , Mapas de Interacción de Proteínas/efectos de los fármacos
4.
Nat Commun ; 12(1): 223, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431820

RESUMEN

Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.


Asunto(s)
Elementos de Facilitación Genéticos , Regiones Promotoras Genéticas , Transcripción Genética , Factor de Unión a CCCTC/metabolismo , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Glicoles/farmacología , Histonas/metabolismo , Humanos , Leucemia/genética , Leucemia/patología , Modelos Genéticos , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/genética , Transcripción Genética/efectos de los fármacos
5.
Ann Hematol ; 100(2): 465-479, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33386934

RESUMEN

Additional sex combs like 1 (ASXL1) mutations are one of the most common molecular biological abnormalities in patients with primary myelofibrosis (PMF), and the effect of these mutations on prognosis remains controversial. Hence, we conducted a meta-analysis to assess the prognostic value and clinical characteristics of ASXL1 mutations in PMF patients. Eligible studies were systematically searched from PubMed, Embase, and the Cochrane Library. We extracted the hazard ratios (HRs) and their 95% confidence intervals (CIs) of overall survival (OS) and leukemia-free survival (LFS), the number of patients transformed to acute leukemia, and clinical characteristics to carry out a meta-analysis by fixed effect model or random effect model according to the heterogeneity between studies. A total of 4501 PMF patients from 16 cohorts of 14 studies were included in this meta-analysis. The results revealed that ASXL1 mutations might predict a shorter OS (HR = 2.30, 95% CI: 1.79-2.94, P < 0.00001) and a higher probability of transformation to acute leukemia (LFS: HR = 1.77, 95% CI: 1.30-2.42, P = 0.0003; the rate of acute leukemia transformation: OR = 2.06, 95% CI: 1.50-2.83, P < 0.00001). Furthermore, ASXL1 mutations were correlated with patients older than 65 years old, male, a lower level of platelet counts, and a higher risk of the international prognostic score system. These findings indicate that ASXL1 mutations have a significant adverse impact on the prognosis of PMF patients and may contribute to risk stratification and prognostic assessment for PMF patients.


Asunto(s)
Carcinogénesis/genética , Leucemia , Mutación , Proteínas de Neoplasias/genética , Mielofibrosis Primaria , Proteínas Represoras/genética , Enfermedad Aguda , Factores de Edad , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia/genética , Leucemia/mortalidad , Masculino , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/mortalidad , Factores Sexuales , Tasa de Supervivencia
6.
Medicine (Baltimore) ; 100(1): e24014, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33429764

RESUMEN

INTRODUCTION: As a hematopoietic carcinogen, benzene induces human leukemia through its active metabolites such as benzoquinone, which may cause oxidative damage to cancer-related nuclear genes by increasing reactive oxygen species (ROS). Mitochondrion is the main regulatory organelle of ROS, genetic abnormality of mitochondrion can impede its regulation of ROS, leading to more severe oxidative damage. Mutations have been related to certain types of cancer in several mitochondrial genes, but they have never been completely analyzed genome-wide in leukemia. PATIENT CONCERNS: The patient was a 52-year-old female who had chronic exposure to benzene for several years. Her symptoms mainly included recurrent dizziness, fatigue, and they had lasted for nearly 8 years and exacerbated in recent weeks before diagnosis. DIAGNOSIS: Samples of peripheral blood were taken from the patient using evacuated tubes with EDTA anticoagulant on the second day of her hospitalization. At the same time blood routine and BCR/ABL genes of leukemic phenotype were tested. Platelets were isolated for mitochondrial DNA (mtDNA) extraction. The genetic analysis of ATP synthase Fo subunit 8 (complex V), ATP synthase Fo subunit 6 (complex V), cytochrome c oxidase subunit 1 (complex IV), cytochrome c oxidase subunit 2 (complex IV), cytochrome c oxidase subunit 3, Cytb, NADH dehydrogenase subunit 1 (complex I) (ND) 1, ND2, ND3, ND4, ND5, ND6, 12S-RNA, 16S-RNA, tRNA-Cysteine, A, N, tRNA-Leucine, E, displacement loop in platelet mtDNA were performed. All the detected gene mutations were validated using the conventional Sanger sequencing method. INTERVENTIONS: The patient received imatinib, a small molecule kinase inhibitor, and symptomatic treatments. OUTCOMES: After 3 months treatment her blood routine test indicators were restored to normal. CONCLUSION: A total of 98 mutations were found, and 25 mutations were frame shift. The ND6 gene mutation rate was the highest among all mutation points. Frame shifts were identified in benzene-induced leukemia for the first time. Many mutations in the platelet mitochondrial genome were identified and considered to be potentially pathogenic in the female patient with benzene-induced leukemia. The mutation rate of platelet mitochondrial genome in the benzene-induced leukemia patient is relatively high, and the complete genome analysis is helpful to fully comprehend the disease characteristics.


Asunto(s)
Plaquetas/patología , Leucemia/etiología , Leucemia/genética , Mitocondrias/genética , Antineoplásicos/uso terapéutico , Benceno/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Genoma Mitocondrial/genética , Genoma Mitocondrial/fisiología , Humanos , Mesilato de Imatinib/uso terapéutico , Persona de Mediana Edad , Mitocondrias/fisiología
7.
Methods Mol Biol ; 2185: 113-134, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33165846

RESUMEN

Recurrent chromosomal translocations define genetic subtypes of childhood leukemia and present the first hit that generates an expanded clone of preleukemic cells in the bone marrow. Most commonly, reverse transcriptase PCR is used to detect these translocations on RNA level. This technique has severe drawbacks, including sensitivity to contamination and instability of RNA. Here, we describe the genomic inverse PCR for exploration of ligated breakpoints (GIPFEL) that overcomes these pitfalls.


Asunto(s)
Células de la Médula Ósea , Leucemia , Lesiones Precancerosas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Femenino , Humanos , Recién Nacido , Leucemia/genética , Leucemia/metabolismo , Leucemia/patología , Masculino , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología
8.
Methods Mol Biol ; 2185: 361-372, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33165860

RESUMEN

Leukemia is a clonal malignant disease originated in a single cell and characterized by the accumulation of abnormal lymphoid cells. The nature of the leukemic stem cell (LSC) has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin. Animal models provide a means to determine the leukemic initiating cell and the causes of malignancy, and to develop new treatments. Recent findings in mice have shown that cancer stem cells can initially arise through a reprogramming-like mechanism when the oncogene expression is targeted to the mouse stem cell compartment (Garcia-Ramirez et al., EMBO J 37(14):298783, 2018; Martin-Lorenzo et al., Cancer Res 78 (10):2669-2679, 2018; Perez-Caro et al., EMBO J 28(1):8-20, 2009; Rodriguez-Hernandez et al., Cancer Res 77(16):4365-4377, 2017). If leukemia arises through reprogramming processes, then perhaps many of the oncogenes that initiate tumor formation might be dispensable for tumor progression and maintenance. Leukemia will be modeled in the mice only if we are able to target the right cancer-initiating cell with a precise given oncogene. In the last years, some examples have already started to appear in the literature showing that targeting oncogene expression to the stem cell compartment in model mice might be the correct way of reproducing the genotype-phenotype correlations found in human leukemias (Garcia-Ramirez et al., EMBO J 37(14):298783, 2018; Martin-Lorenzo et al., Cancer Res 78 (10):2669-2679, 2018; Perez-Caro et al., EMBO J 28(1):8-20, 2009; Rodriguez-Hernandez et al., Cancer Res 77(16):4365-4377, 2017). This chapter addresses how to generate LSCs by transgenesis in a way that makes the resulting animal models valuable tools to reproduce and understand leukemogenesis, and for the development of therapeutic applications like drug discovery or biomarker identification.


Asunto(s)
Transformación Celular Neoplásica , Técnicas de Reprogramación Celular , Regulación Leucémica de la Expresión Génica , Leucemia , Células Madre Neoplásicas/metabolismo , Oncogenes , Animales , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patología , Ratones , Células Madre Neoplásicas/patología
11.
Sci Rep ; 10(1): 22086, 2020 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-33328565

RESUMEN

Effective phagocytosis is crucial for host defense against pathogens. Macrophages entrap pathogens into a phagosome and subsequently acidic lysosomes fuse to the phagosome. Previous studies showed the pivotal role of actin-remodeling mediated by phosphoinositide-related signaling in phagosome formation, but the mechanisms of phagosome-lysosome fusion remain unexplored. Here we show that in complement-mediated phagocytosis, phagosome-lysosome fusion requires the disappearance of F-actin structure surrounding the phagosome and a tyrosine kinase Syk plays a key role in this process. Using macrophage-like differentiated HL60 and Syk-knockout (Syk-KO) HL60 cells, we found that Syk-KO cells showed insufficient phagosome acidification caused by impaired fusion with lysosomes and permitted the survival of Candida albicans in complement-mediated phagocytosis. Phagosome tracking analysis showed that during phagosome internalization process, F-actin surrounding phagosomes disappeared in both parental and Syk-KO cells but this structure was reconstructed immediately only in Syk-KO cells. In addition, F-actin-stabilizing agent induced a similar impairment of phagosome-lysosome fusion. Collectively, Syk-derived signaling facilitates phagosome-lysosome fusion by regulating actin-remodeling.


Asunto(s)
Leucemia/genética , Fagocitosis/genética , Fagosomas/genética , Quinasa Syk/genética , Actinas/genética , Línea Celular Tumoral , Proteínas del Sistema Complemento/genética , Regulación Leucémica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Inactivación de Genes , Humanos , Leucemia/patología , Lisosomas/genética , Macrófagos/metabolismo , Macrófagos/patología
12.
Medicine (Baltimore) ; 99(50): e23569, 2020 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-33327316

RESUMEN

The SET nuclear proto-oncogene (SET)-nucleoporin (NUP) 214 fusion gene (SET-NUP214) is a rare leukemia fusion gene. Due to the limited number of samples with SET-NUP214 fusion gene in previous studies, the significance of SET-NUP214 for measurable residual disease (MRD) monitoring in patients with acute leukemia (AL) is still unclear. Our study aimed to observe the dynamic changes in SET-NUP214 expression before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and analyzed whether SET-NUP214 could be used to evaluate MRD status. Our study included 24 AL patients who were newly diagnosed with SET-NUP214 fusion gene and they all received allo-HSCT. Their MRD was evaluated by monitoring SET-NUP214 fusion gene and leukemia-associated immunophenotype (LAIP). The median follow-up time was 501 days (56-2208 days). Of the enrolled patients, 6 (25%) patients died, including 3 (12.5%) patients died of leukemia relapse. Total 5 (20.8%) patients experienced hematological relapse at a median of 225 days (56-1057 days) post-transplantation. The SET-NUP214 median expression level at diagnosis was 405.1% (14.6%-1482.4%). SET-NUP214 gene expression generally became positive prior to flow cytometry results. In addition, the Kaplan-Meier survival curves analysis showed that those who had SET-NUP214 positive (SET-NUP214+) post-transplantation had a higher 2-year cumulative incidence of leukemia relapse (CIR) of 43.7 ±â€Š18.8% (P < .05). However, there was no significant difference between SET-NUP214 positive and SET-NUP214 negative patients with regard to their 2-year overall survival (OS) (82.5 ±â€Š11.3 vs 64.6 ±â€Š17.5%, respectively, P = .271). ROC curve analysis turned out that the area under the ROC curve (AUC) was 0.916 (95% CI: 0.784-1.0; P = .005). In conclusion, SET-NUP214 fusion gene determined by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) could be used to evaluate MRD status after allo-HSCT. Patients with positive SET-NUP214 expression after transplantation will have a poor prognosis.


Asunto(s)
Proteínas de Unión al ADN/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Chaperonas de Histonas/genética , Leucemia/genética , Proteínas de Complejo Poro Nuclear/genética , Fusión de Oncogenes/genética , Adolescente , Adulto , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Estimación de Kaplan-Meier , Leucemia/diagnóstico , Leucemia/mortalidad , Leucemia/terapia , Masculino , Persona de Mediana Edad , Neoplasia Residual , Pronóstico , Curva ROC , Estudios Retrospectivos , Análisis de Supervivencia , Adulto Joven
13.
Medicine (Baltimore) ; 99(44): e23006, 2020 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-33126384

RESUMEN

Interleukin-10(IL-10) is an immunosuppressive cytokine and plays an important role in inflammation and cancers. Numerous studies have explored the association between single nucleotide polymorphisms of IL-10 and leukemia, but their results were conflicting, so we performed this meta-analysis to elucidate the association between 3 common single nucleotide polymorphisms of IL-10 (rs1800896, rs1800871 and rs1800872) and risk of leukemia.We conducted a comprehensive research in Pubmed, Chinese Biomedical Literature Database disc and Embase using related terms. After strict selection, 18 studies with 2264 cases and 3846 controls were included into this meta-analysis. Odds ratio and 95% confidence interval were used to evaluate the strength of the association.We found that polymorphism of IL-10 -1082A/G was associated with decreased risk of leukemia both in overall analysis and in stratified analysis according to ethnicity and cancer type. A strong relationship was also uncovered between polymorphism of IL-10 -592C/A and increased risk of leukemia in non-Chinese.GG genotype of IL-10 -1082A/G is associated with decreased risk of leukemia, especially chronic lymphocytic leukemia. CC genotype of -592C/A is associated with decreased risk of leukemia in non-Chinese.


Asunto(s)
Predisposición Genética a la Enfermedad , Interleucina-10/genética , Leucemia/genética , Estudios de Casos y Controles , Grupos Étnicos , Humanos , Polimorfismo de Nucleótido Simple , Riesgo
14.
Nat Commun ; 11(1): 4056, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32792483

RESUMEN

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid ß-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.


Asunto(s)
Autofagia/fisiología , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia/metabolismo , Mitocondrias/metabolismo , Animales , Autofagia/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/fisiología , Citometría de Flujo , Humanos , Leucemia/genética , Leucemia Mieloide Aguda/patología , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/fisiología , Lipogénesis/genética , Lipogénesis/fisiología , Ratones , Mitocondrias/genética , Oxidación-Reducción , Fosforilación Oxidativa
15.
Proc Natl Acad Sci U S A ; 117(33): 19982-19993, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32753382

RESUMEN

The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1-RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.


Asunto(s)
Leucemia/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Leucemia/genética , Leucemia/fisiopatología , Ratones , Ratones Endogámicos BALB C , Necroptosis , Unión Proteica , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-myc/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Transducción de Señal
16.
Ann Hematol ; 99(10): 2231-2242, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32621182

RESUMEN

Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Hematológicas/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-myc/fisiología , ARN Largo no Codificante/genética , ARN Neoplásico/genética , Autorrenovación de las Células/genética , Genes myc , Hematopoyesis/genética , Humanos , Leucemia/genética , Linfocitos/metabolismo , Linfocitos/patología , Linfoma/genética , Mieloma Múltiple/genética , Células Mieloides/metabolismo , Células Mieloides/patología , Nicho de Células Madre
17.
Nat Commun ; 11(1): 3455, 2020 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-32661245

RESUMEN

CRISPR-based genetic screening has revolutionized cancer drug target discovery, yet reliable, multiplex gene editing to reveal synergies between gene targets remains a major challenge. Here, we present a simple and robust CRISPR-Cas12a-based approach for combinatorial genetic screening in cancer cells. By engineering the CRISPR-AsCas12a system with key modifications to the Cas protein and its CRISPR RNA (crRNA), we can achieve high efficiency combinatorial genetic screening. We demonstrate the performance of our optimized AsCas12a (opAsCas12a) through double knockout screening against epigenetic regulators. This screen reveals synthetic sick interactions between Brd9&Jmjd6, Kat6a&Jmjd6, and Brpf1&Jmjd6 in leukemia cells.


Asunto(s)
Proteínas Bacterianas/genética , Proteínas Asociadas a CRISPR/genética , Sistemas CRISPR-Cas , Endodesoxirribonucleasas/genética , Edición Génica , Regulación Leucémica de la Expresión Génica , Leucemia/genética , Animales , Proliferación Celular , Epigénesis Genética , Biblioteca de Genes , Ingeniería Genética , Genoma Humano , Células HEK293 , Humanos , Células K562 , Ratones , Células 3T3 NIH , Dominios Proteicos , ARN Guia/genética
18.
Leukemia ; 34(10): 2561-2575, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32690881

RESUMEN

DNA is compacted into higher order structures that have major implications in gene regulation. These structures allow for long-range interactions of DNA elements, such as the association of promoters with their cognate enhancers. In recent years, mutations in genes that control these structures, including the cohesin-complex and the insulator-binding protein CTCF, have been found in a spectrum of hematologic disorders, and especially in acute leukemias. Cohesin and CTCF are critical for mediating looping and establishing boundaries within chromatin. Cells that harbor mutations in these genes display aberrant chromatin architecture and resulting differences in gene expression that contribute to leukemia initiation and progression. Here, we provide detailed discussion of the nature of 3D interactions and the way that they are disrupted in acute leukemia. Continued research in this area will provide new insights into the mechanisms of leukemogenesis and may shed light on novel treatment strategies.


Asunto(s)
Cromatina/metabolismo , Leucemia/metabolismo , Enfermedad Aguda , Factor de Unión a CCCTC/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia/genética , Mutación
19.
Cancer Treat Rev ; 88: 102026, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32592909

RESUMEN

Progress in cancer therapy changed the outcome of many patients and moved therapy from chemotherapy agents to targeted drugs. Targeted drugs already changed the clinical practice in treatment of leukemias, such as imatinib (BCR/ABL inhibitor) in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), ibrutinib (Bruton's tyrosine kinase inhibitor) in chronic lymphocytic leukemia (CLL), venetoclax (BCL2 inhibitor) in CLL and acute myeloid leukemia (AML) or midostaurin (FLT3 inhibitor) in AML. In this review, we focused on DNA damage response (DDR) inhibition, specifically on inhibition of ATR-CHK1 pathway. Cancer cells harbor often defects in different DDR pathways, which render them vulnerable to DDR inhibition. Some DDR inhibitors showed interesting single-agent activity even in the absence of cytotoxic drug especially in cancers with underlying defects in DDR or DNA replication. Almost no mutations were found in ATR and CHEK1 genes in leukemia patients. Together with the fact that ATR-CHK1 pathway is essential for cell development and survival of leukemia cells, it represents a promising therapeutic target for treatment of leukemia. ATR-CHK1 inhibition showed excellent results in preclinical testing in acute and chronic leukemias. However, results in clinical trials are so far insufficient. Therefore, the ongoing and future clinical trials will decide on the success of ATR/CHK1 inhibitors in clinical practice of leukemia treatment.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Leucemia/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Enfermedad Aguda , Animales , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Enfermedad Crónica , Daño del ADN , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patología , Terapia Molecular Dirigida , Ensayos Clínicos Controlados Aleatorios como Asunto
20.
Leuk Res ; 95: 106386, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32512379

RESUMEN

Myeloid neoplasms (MN) are usually sporadic late-onset cancers; nevertheless, growing evidence suggests that ∼5% of the cases could emerge as a consequence of inherited predisposition. Distinguishing somatic from germline variants is of vital importance, in order to establish an appropriate individualized management and counsel the patients and their relatives. Since many of the genes associated with myeloid neoplasm germline predisposition (MNGP) are also affected in sporadic MN, we intended to design a strategy to identify potentially inherited variants in a tumor only NGS panel in a cohort of 299 patients with a variety of MN. We considered as indicative of potential inherited origin, variants detected in BM sample at a ∼50% VAF classified as pathogenic, likely pathogenic or of unknown significance detected in MNGP-related genes. A total of 104 suspicious variants from 90 patients were filtered-in in tumor samples. Mutational patterns, follow-up data, and sequencing of a range of non-myeloid tissues were used for narrowing down the list of suspicious variants, and ultimately discriminate their nature. Our data supports the importance of considering variants found upon tumor-only sequencing as potentially of germline origin, and we offer a pipeline to define the nature of the variants.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Leucemia/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética
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