RESUMEN
In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the formation of microspeckles. However, our understanding, largely learned from morphological observations, lacks insight into the mechanisms behind PML/RARα-mediated microspeckle formation and its role in APL leukemogenesis. This study presents evidence uncovering liquid-liquid phase separation (LLPS) as a key mechanism in the formation of PML/RARα-mediated microspeckles. This process is facilitated by the intrinsically disordered region containing a large portion of PML and a smaller segment of RARα. We demonstrate the coassembly of bromodomain-containing protein 4 (BRD4) within PML/RARα-mediated condensates, differing from wild-type PML-formed NBs. In the absence of PML/RARα, PML NBs and BRD4 puncta exist as two independent phases, but the presence of PML/RARα disrupts PML NBs and redistributes PML and BRD4 into a distinct phase, forming PML/RARα-assembled microspeckles. Genome-wide profiling reveals a PML/RARα-induced BRD4 redistribution across the genome, with preferential binding to super-enhancers and broad-promoters (SEBPs). Mechanistically, BRD4 is recruited by PML/RARα into nuclear condensates, facilitating BRD4 chromatin binding to exert transcriptional activation essential for APL survival. Perturbing LLPS through chemical inhibition (1, 6-hexanediol) significantly reduces chromatin co-occupancy of PML/RARα and BRD4, attenuating their target gene activation. Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.
Asunto(s)
Proteínas de Ciclo Celular , Leucemia Promielocítica Aguda , Proteínas de Fusión Oncogénica , Factores de Transcripción , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Fusión Oncogénica/genética , Línea Celular Tumoral , Regulación Leucémica de la Expresión Génica , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteína de la Leucemia Promielocítica/metabolismo , Proteína de la Leucemia Promielocítica/genética , Separación de Fases , Proteínas que Contienen BromodominioRESUMEN
Although immunotherapy is expanding treatment options for cancer patients, the prognosis of advanced cancer remains poor, and these patients must contend with both cancers and cancer-related thrombotic events. In particular, immune checkpoint inhibitors are associated with an increased risk of atherosclerotic thrombotic events. Given the fundamental role of platelets in atherothrombosis, co-administration of antiplatelet agents is always indicated. Platelets are also involved in all steps of cancer progression. Classical antithrombotic drugs can cause inevitable hemorrhagic side effects due to blocking integrin ß3 bidirectional signaling, which regulates simultaneously thrombosis and hemostasis. Meanwhile, many promising new targets are emerging with minimal bleeding risk and desirable anti-tumor effects. This review will focus on the issue of thrombosis during immune checkpoint inhibitor treatment and the role of platelet activation in cancer progression as well as explore the mechanisms by which novel antiplatelet therapies may exert both antithrombotic and antitumor effects without excessive bleeding risk.
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Fibrinolíticos , Hemorragia , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Trombosis , Humanos , Trombosis/etiología , Trombosis/prevención & control , Hemorragia/etiología , Hemorragia/prevención & control , Hemorragia/inducido químicamente , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Fibrinolíticos/uso terapéutico , Fibrinolíticos/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , AnimalesRESUMEN
Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFß::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFß::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Animales , Subunidad beta del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Ratones , Regulación Leucémica de la Expresión Génica , Línea Celular TumoralRESUMEN
Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.
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Resistencia a Antineoplásicos , Leucemia Mieloide Aguda , Mutación , Factor de Empalme U2AF , Humanos , Factor de Empalme U2AF/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Resistencia a Antineoplásicos/genética , Biosíntesis de Proteínas/efectos de los fármacos , ARN Mensajero/genética , Empalme del ARN/genética , Animales , Estudios Retrospectivos , Ratones , Línea Celular Tumoral , Factor 4A Eucariótico de Iniciación/genética , Factor 4A Eucariótico de Iniciación/metabolismoRESUMEN
Acute promyelocytic leukemia (APL) represents a paradigm for targeted differentiation therapy, with a minority of patients experiencing treatment failure and even early death. We here report a comprehensive single-cell analysis of 16 APL patients, uncovering cellular compositions and their impact on all-trans retinoic acid (ATRA) response in vivo and early death. We unveil a cellular differentiation hierarchy within APL blasts, rooted in leukemic stem-like cells. The oncogenic PML/RARα fusion protein exerts branch-specific regulation in the APL trajectory, including stem-like cells. APL cohort analysis establishes an association of leukemic stemness with elevated white blood cell counts and FLT3-ITD mutations. Furthermore, we construct an APL-specific stemness score, which proves effective in assessing early death risk. Finally, we show that ATRA induces differentiation of primitive blasts and patients with early death exhibit distinct stemness-associated transcriptional programs. Our work provides a thorough survey of APL cellular hierarchies, offering insights into cellular dynamics during targeted therapy.
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Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Tretinoina/farmacología , Diferenciación Celular , Línea Celular Tumoral , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismoRESUMEN
The chromosome 20 long arm (20q) is one of the genomic hotspots where copy number alterations frequently occur in multiple types of tumors. However, it remains elusive which genes are implicated in 20q-related tumorigenesis. Here, by querying TCGA and GEO databases, we observed frequent copy number amplification at 20q and the chromosome subband 20q13.33 was amplificated in multiple cancers. Among those genes at 20q13.33, PSMA7 was found with the strongest correlation with cancers. Further analysis revealed that PSMA7 amplification was the most frequent genetic alteration event conferring adverse prognosis in various cancers. Consistent with the strong positive correlation between PSMA7 amplification and gene expression, elevated PSMA7 expression was observed in 20 of 33 types of cancers with a close link to adverse outcomes in certain tumors. In addition, PSMA7 was essential for the growth of almost 1095 cancer lines. Mechanistically, aberrant PSMA7 most probably influenced the proteasome and protease-related pathways to promote tumorigenesis and might be antagonized by several compounds, e.g., Docetaxel in relevant cancers. The current in-depth pan-cancer analysis refines our understanding of the crucial oncogenic role of copy number amplifications at PSMA7 loci at the novel chromosome amplicon 20q13.33 across different tumors.
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Transformación Celular Neoplásica , Genoma , Humanos , Transformación Celular Neoplásica/genética , Variaciones en el Número de Copia de ADN , Pronóstico , Cromosomas/metabolismo , Amplificación de Genes , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
Through targeting essential cellular regulators for ubiquitination and serving as a major platform for discovering proteolysis-targeting chimera (PROTAC) drugs, Cullin-2 (CUL2)-RING ubiquitin ligases (CRL2s) comprise an important family of CRLs. The founding members of CRLs, the CUL1-based CRL1s, are known to be activated by CAND1, which exchanges the variable substrate receptors associated with the common CUL1 core and promotes the dynamic assembly of CRL1s. Here we find that CAND1 inhibits CRL2-mediated protein degradation in human cells. This effect arises due to altered binding kinetics, involving CAND1 and CRL2VHL, as we illustrate that CAND1 dramatically increases the dissociation rate of CRL2s but barely accelerates the assembly of stable CRL2s. Using PROTACs that differently recruit neo-substrates to CRL2VHL, we demonstrate that the inhibitory effect of CAND1 helps distinguish target proteins with different affinities for CRL2s, presenting a mechanism for selective protein degradation with proper pacing in the changing cellular environment.
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Proteínas Cullin , Ubiquitina , Humanos , Ubiquitina/metabolismo , Proteínas Cullin/metabolismo , Especificidad por Sustrato , Proteínas Portadoras/metabolismo , Ubiquitinación , Ubiquitina-Proteína Ligasas/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Understanding the molecular pathogenesis of acute myeloid leukemia (AML) with well-defined genomic abnormalities has facilitated the development of targeted therapeutics. Patients with t(8;21) AML frequently harbor a fusion gene RUNX1-RUNX1T1 and KIT mutations as "secondary hit", making the disease one of the ideal models for exploring targeted treatment options in AML. In this study we investigated the combination therapy of agents targeting RUNX1-RUNX1T1 and KIT in the treatment of t(8;21) AML with KIT mutations. We showed that the combination of eriocalyxin B (EriB) and homoharringtonine (HHT) exerted synergistic therapeutic effects by dual inhibition of RUNX1-RUNX1T1 and KIT proteins in Kasumi-1 and SKNO-1 cells in vitro. In Kasumi-1 cells, the combination of EriB and HHT could perturb the RUNX1-RUNX1T1-responsible transcriptional network by destabilizing RUNX1-RUNX1T1 transcription factor complex (AETFC), forcing RUNX1-RUNX1T1 leaving from the chromatin, triggering cell cycle arrest and apoptosis. Meanwhile, EriB combined with HHT activated JNK signaling, resulting in the eventual degradation of RUNX1-RUNX1T1 by caspase-3. In addition, HHT and EriB inhibited NF-κB pathway through blocking p65 nuclear translocation in two different manners, to synergistically interfere with the transcription of KIT. In mice co-expressing RUNX1-RUNX1T1 and KITN822K, co-administration of EriB and HHT significantly prolonged survival of the mice by targeting CD34+CD38- leukemic cells. The synergistic effects of the two drugs were also observed in bone marrow mononuclear cells (BMMCs) of t(8;21) AML patients. Collectively, this study reveals the synergistic mechanism of the combination regimen of EriB and HHT in t(8;21) AML, providing new insight into optimizing targeted treatment of AML.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Diterpenos , Leucemia Mieloide Aguda , Humanos , Animales , Ratones , Homoharringtonina/farmacología , Homoharringtonina/uso terapéutico , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/uso terapéutico , Translocación Genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMEN
Plants appear quiet: quietly, they break the ground, expand leaves, search for resources, alert each other to invaders, and heal their own wounds. In contrast to the stationary appearance, the inside world of a plant is full of movements: cells divide to increase the body mass and form new organs; signaling molecules migrate among cells and tissues to drive transcriptional cascades and developmental programs; macromolecules, such as RNAs and proteins, collaborate with different partners to maintain optimal organismal function under changing cellular and environmental conditions. All these activities require a dynamic yet appropriately controlled molecular network in plant cells. In this short review, we used the regulation of cullin-RING ubiquitin ligases (CRLs) as an example to discuss how dynamic biochemical processes contribute to plant development. CRLs comprise a large family of modular multi-unit enzymes that determine the activity and stability of diverse regulatory proteins playing crucial roles in plant growth and development. The mechanism governing the dynamic assembly of CRLs is essential for CRL activity and biological function, and it may provide insights and implications for the regulation of other dynamic multi-unit complexes involved in fundamental processes such as transcription, translation, and protein sorting in plants.
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Proteínas Cullin , Ubiquitina , Ubiquitina/metabolismo , Proteínas Cullin/química , Proteínas Cullin/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Transducción de Señal , Unión ProteicaAsunto(s)
Leucemia Promielocítica Aguda , Trombocitemia Esencial , Humanos , Trombocitemia Esencial/genética , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Translocación Genética , Evolución Clonal/genéticaRESUMEN
Neoantigens derived from non-synonymous somatic mutations are restricted to malignant cells and are thus considered ideal targets for T cell receptor (TCR)-based immunotherapy. Adoptive transfer of T cells bearing neoantigen-specific TCRs exhibits the ability to preferentially target tumor cells while remaining harmless to normal cells. High-avidity TCRs specific for neoantigens expressed on AML cells have been identified in vitro and verified using xenograft mouse models. Preclinical studies of these neoantigen-specific TCR-T cells are underway and offer great promise as safe and effective therapies. Additionally, TCR-based immunotherapies targeting tumor-associated antigens are used in early-phase clinical trials for the treatment of AML and show encouraging anti-leukemic effects. These clinical experiences support the application of TCR-T cells that are specifically designed to recognize neoantigens. In this review, we will provide a detailed profile of verified neoantigens in AML, describe the strategies to identify neoantigen-specific TCRs, and discuss the potential of neoantigen-specific T-cell-based immunotherapy in AML.
RESUMEN
Acute promyelocytic leukemia (APL) is characterized by the balanced translocation of chromosomes 15 and 17, resulting in the formation of PML-RARA fusion gene. More than 98% of APL have PML-RARA fusion, and less than 2% have other types of RARA gene partners, which named variant APL (vAPL). In the present study, we reported a vAPL with BCOR-RARA, which was the third case of BCOR-RARA APL published. The patient achieved complete remission (CR) with all-trans retinoic acid (ATRA) monotherapy, and molecular CR with ATRA plus standard chemotherapy. After that, he underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and ATRA maintenance and maintained a molecular CR status. This case provided valuable insights into the accurate identification of vAPL. Moreover, ATRA combined with chemotherapy followed by allo-HSCT was suggested as an optimal choice for those vAPL patients who had a high risk of relapse.
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In sign language video, the hand region is small, the resolution is low, the motion speed is fast, and there are cross occlusion and blur phenomena, which have a great impact on sign language recognition rate and speed, and are important factors restricting sign language recognition performance. To solve these problems, this paper proposes an improved 3D-ResNet sign language recognition algorithm with enhanced hand features, aiming to highlight the features of both hands, solve the problem of missing more effective information when relying only on global features, and improve the accuracy of sign language recognition. The proposed method has two improvements. Firstly, the algorithm detects the left and right hand regions based on the improved EfficientDet network, uses the improved Bi-FPN module and dual channel and spatial attention module are used to enhance the detection ability of the network for small targets like hand. Secondly, the improved residual module is used to improve the 3D-ResNet18 network to extract sign language features. The global, the left-hand and the right-hand image sequences are divided into three branches for feature extraction and fusion, so as to strengthen the attention to hand features, strengthen the representation ability of sign language features, and achieve the purpose of improving the accuracy of sign language recognition. In order to verify the performance of this algorithm, a series of experiments are carried out on CSL dataset. For example, in the experiments of hand detection algorithm and sign language recognition algorithm, the performance indicators such as Top-N, mAP, FLOPs and Parm are applied to find the optimal algorithm framework. The experimental results show that the Top1 recognition accuracy of this algorithm reaches 91.12%, which is more than 10% higher than that of C3D, P3D and 3D-ResNet basic networks. From the performance indicators of Top-N, mAP, FLOPs, Parm and so on, the performance of the algorithm in this paper is better than several algorithms in recent three years, such as I3D+BLSTM, B3D ResNet, AM-ResC3D+RCNN and so on. The results show that the hand detection network with enhanced hand features and three-dimensional convolutional neural network proposed in this paper can achieve higher accuracy of sign language recognition.
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Algoritmos , Lengua de Signos , Humanos , Redes Neurales de la Computación , ManoRESUMEN
In patients with acute promyelocytic leukemia (APL), intracranial hemorrhage (ICH), if not identified promptly, could be fatal. It is the leading cause of failure of induction and early death. Thus, biomarkers that could promptly predict severe complications are critical. Here, cytokine differences between patients with APL with and without ICH were investigated to develop predictive models for this complication. The initial cytokine profiling using plasma samples from 39 patients and 18 healthy donors found a series of cytokines that were remarkedly different between patients with APL and healthy controls. The APL patients were subsequently divided into high and low white blood cell count groups. Results showed that tumor necrosis factor a and interleukin 8 (IL-8) were vital in distinguishing patients with APL who did or did not develop ICH. In addition, verification in 81 patients with APL demonstrated that the two cytokines were positively correlated with the cumulative incidence of ICH. Finally, in-vitro and in-vivo experimental evidence were provided to show that IL-8 influenced the migration of APL-derived NB4 cells and impaired the blood-brain barrier in PML/RARα positive blast-transplanted FVB/NJ mice. These assessments may facilitate the early warning of ICH and reduce future mortality levels in APL.
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Leucemia Promielocítica Aguda , Ratones , Animales , Leucemia Promielocítica Aguda/complicaciones , Tretinoina/farmacología , Interleucina-8 , Factor de Necrosis Tumoral alfa , Citocinas , Hemorragias Intracraneales/etiología , Proteínas de Fusión OncogénicaAsunto(s)
ADN Mitocondrial , Leucemia Mieloide Aguda , Humanos , Inversión Cromosómica , Subunidad beta del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Mutación , Cadenas Pesadas de Miosina/genética , Proteínas de Fusión Oncogénica/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Mitocondrias/genéticaRESUMEN
Genetic alternations can occur at noncoding regions, but how they contribute to cancer pathogenesis is poorly understood. Here, we established a mutational landscape of cis-regulatory regions (CREs) in acute promyelocytic leukemia (APL) based on whole-genome sequencing analysis of paired tumor and germline samples from 24 patients and epigenetic profiling of 16 patients. Mutations occurring in CREs occur preferentially in active enhancers bound by the complex of master transcription factors in APL. Among significantly enriched mutated CREs, we found a recurrently mutated region located within the third intron of WT1, an essential regulator of normal and malignant hematopoiesis. Focusing on noncoding mutations within this WT1 intron, an analysis on 169 APL patients revealed that somatic mutations were clustered into a focal hotspot region, including one site identified as a germline polymorphism contributing to APL risk. Significantly decreased WT1 expression was observed in APL patients bearing somatic and/or germline noncoding WT1 variants. Furthermore, biallelic WT1 inactivation was recurrently found in APL patients with noncoding WT1 variants, which resulted in the complete loss of WT1. The high incidence of biallelic inactivation suggested the tumor suppressor activity of WT1 in APL. Mechanistically, noncoding WT1 variants disrupted MYB binding on chromatin and suppressed the enhancer activity and WT1 expression through destroying the chromatin looping formation. Our study highlights the important role of noncoding variants in the leukemogenesis of APL.
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Leucemia Promielocítica Aguda , Proteínas Proto-Oncogénicas c-myb , Proteínas WT1 , Cromatina/metabolismo , Mutación de Línea Germinal , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Polimorfismo de Nucleótido Simple , Unión Proteica/genética , Proteínas Proto-Oncogénicas c-myb/genética , Proteínas Proto-Oncogénicas c-myb/metabolismo , Proteínas WT1/genéticaRESUMEN
Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia is obscure. Here, we conducted a retrospective study containing 1,412 cases (319 newly diagnosed APL patients, 393 newly diagnosed non-APL acute myeloid leukemia patients, and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non- APL and control groups. Using clinical data, we revealed that hypertriglyceridemia served as a risk factor for early death in APL patients, and there was a positive correlation between triglyceride levels and leukocyte counts. RNA sequencing analysis of APL patients having high or normal triglyceride levels highlighted the contribution of peroxisome proliferatoractivated receptor-α (PPARα), a crucial regulator of cell metabolism and a transcription factor involved in cancer development. The genome-wide chromatin occupancy of PPARα revealed that PPARα co-existed with PML/RARα within the super-enhancer regions to promote cell proliferation. PPARα knockdown affected the expression of target genes responsible for APL proliferation, including FLT3, and functionally inhibited the proliferation of APL cells. Moreover, in vivo results in mice having high fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemic burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL proliferation and high triglyceride levels and provide a genetic link to PPARα-mediated hyperlipidemia in APL.
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Hiperlipidemias , Hipertrigliceridemia , Leucemia Promielocítica Aguda , Ratones , Animales , Leucemia Promielocítica Aguda/patología , PPAR alfa , Tretinoina/farmacología , Estudios Retrospectivos , Proteínas de Fusión Oncogénica/genética , TriglicéridosRESUMEN
Colorectal neoplasia differentially expressed (CRNDE) is an oncogenic long noncoding RNA (lncRNA). Increased CRNDE expression was initially discovered in colorectal cancer and then in a variety of solid tumors and hematological malignancies. CRNDE participates in multiple biological processes, such as cell proliferation, differentiation, migration, and apoptosis. CRNDE has been shown to modulate target gene expression through multiple mechanisms, including transcriptional regulation, post-transcriptional regulation, and competition for microRNA (miRNA) binding. In this review, we summarize the evidence that supports CRNDE in the diagnosis and prognosis predicting of cancers. The functional roles and molecular mechanisms of CRNDE are further described for major types of solid tumors and hematological malignancies. The therapeutic potential of CRNDE as a target for research and development is also discussed.
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Pemphigus is an autoimmune skin disease. Ectopic lymphoid-like structures (ELSs) were found to be commonly present in the pemphigus lesions, presumably supporting in situ desmoglein (Dsg)-specific antibody production. Yet functional phenotypes and the regulators of Lymphoid aggregates in pemphigus lesions remain largely unknown. Herein, we used microarray technology to profile the gene expression in skin lesion infiltrating mononuclear cells (SIMC) from pemphigus patients. On top of that, we compared SIMC dataset to peripheral blood mononuclear cells (PBMC) dataset to characterize the unique role of SIMC. Functional enrichment results showed that mononuclear cells in skin lesions and peripheral blood both had over-represented IL-17 signaling pathways while neither was characterized by an activation of type I Interferon signaling pathways. Cell-type identification with relative subsets of known RNA transcripts (CIBERSORT) results showed that naïve natural killer cells (NK cells) were significantly more abundant in pemphigus lesions, and their relative abundance positively correlated with B cells abundance. Meanwhile, plasma cells population highly correlated with type 1 macrophages (M1) abundance. In addition, we also identified a lncRNA LINC01588 which might epigenetically regulate T helper 17 cells (Th17)/regulatory T cells (Treg) balance via the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Here, we provide the first transcriptomic characterization of lesion infiltrating immune cells which illustrates a distinct interplay network between adaptive and innate immune cells. It helps discover new regulators of local immune response, which potentially will provide a novel path forward to further uncover pemphigus pathological mechanisms and develop targeted therapy.