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Eritroblastos , Leucemia Eritroblástica Aguda , Síndromes Mielodisplásicos , Derrame Pleural , Humanos , Eritroblastos/patología , Eritroblastos/metabolismo , Leucemia Eritroblástica Aguda/patología , Leucemia Eritroblástica Aguda/diagnóstico , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/diagnóstico , Masculino , Derrame Pleural/patología , Derrame Pleural/etiología , Anciano , FemeninoRESUMEN
The clinical impact of therapy-related acute leukemias is increasing with the extension of cancer-related survival; however, the origins remain largely unknown. Acute erythroleukemia (AEL), a rare unfavorable type of myeloid neoplasia, may also develop secondary to cytotoxic therapy. The disorder is featured by specific genetic alterations, most importantly multi-allelic mutations of the TP53 gene. While AEL might appear as a part of the therapy-related MDS/AML, spectrum information regarding the genetic complexity and progression is largely missing. We present two AEL cases arising after cytotoxic therapy and melphalan-based myeloablation/autologous peripheral stem cell transplantation due to multiple myeloma (MM). As stated, multiple pathogenic TP53 variants were present unrelated to preexisting MM, in parallel with uninvolved/wild-type hemopoiesis. Potential mechanisms of leukemic transformation are discussed, which include (1) preexisting preneoplastic hemopoietic stem cells (HSC) serving as the common origin for both MM and AEL, (2) the generation and intramedullary survival of p53-deficient post-chemotherapy HSCs, (3) reinoculation of mobilized autologous TP53 mutated HSCs, and (4) melphalan treatment-related late-onset myelodysplasia/leukemia with newly acquired TP53 mutations.
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Leucemia Eritroblástica Aguda , Mieloma Múltiple , Trasplante Autólogo , Mieloma Múltiple/terapia , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Humanos , Persona de Mediana Edad , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patología , Leucemia Eritroblástica Aguda/terapia , Masculino , Proteína p53 Supresora de Tumor/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Transformación Celular Neoplásica/genética , Mutación , Femenino , Melfalán/uso terapéutico , Melfalán/administración & dosificación , Anciano , Quimioradioterapia/métodos , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/terapia , Neoplasias Primarias Secundarias/genéticaRESUMEN
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.
Asunto(s)
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
Acute Erythroid Leukemia (AEL) is a rare and aggressive subtype of Acute Myeloid Leukemia (AML). In 2022, the World Health Organization (WHO) defined AEL as a biopsy with ≥30% proerythroblasts and erythroid precursors that account for ≥80% of cellularity. The International Consensus Classification refers to this neoplasm as "AML with mutated TP53". Classification entails ≥20% blasts in blood or bone marrow biopsy and a somatic TP53 mutation (VAF > 10%). This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions. Transgenic mouse models have implicated several molecules in the pathogenesis of AEL, including transcriptional master regulator GATA1 (involved in erythroid differentiation), master oncogenes, and CDX4. Recent studies have also characterized AEL by epigenetic regulator mutations and transcriptome subgroups. AEL patients have overall poor clinical outcomes, mostly related to their poor response to the standard therapies, which include hypomethylating agents and intensive chemotherapy. Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach but requires deep remission, which is very challenging for these patients. Age, AlloBMT, and a history of antecedent myeloid neoplasms further affect the outcomes of these patients. In this review, we will summarize the diagnostic criteria of AEL, review the current insights into the biology of AEL, and describe the treatment options and outcomes of patients with this disease.
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Leucemia Eritroblástica Aguda , Humanos , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/terapia , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/patología , Animales , Mutación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
G protein pathway suppressor 2 (GPS2) has been shown to play a pivotal role in human and mouse definitive erythropoiesis in an EKLF-dependent manner. However, whether GPS2 affects human primitive erythropoiesis is still unknown. This study demonstrated that GPS2 positively regulates erythroid differentiation in K562 cells, which have a primitive erythroid phenotype. Overexpression of GPS2 promoted hemin-induced hemoglobin synthesis in K562 cells as assessed by the increased percentage of benzidine-positive cells and the deeper red coloration of the cell pellets. In contrast, knockdown of GPS2 inhibited hemin-induced erythroid differentiation of K562 cells. GPS2 overexpression also enhanced erythroid differentiation of K562 cells induced by cytosine arabinoside (Ara-C). GPS2 induced hemoglobin synthesis by increasing the expression of globin and ALAS2 genes, either under steady state or upon hemin treatment. Promotion of erythroid differentiation of K562 cells by GPS2 mainly relies on NCOR1, as knockdown of NCOR1 or lack of the NCOR1-binding domain of GPS2 potently diminished the promotive effect. Thus, our study revealed a previously unknown role of GPS2 in regulating human primitive erythropoiesis in K562 cells.
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Diferenciación Celular , Eritropoyesis , Hemina , Leucemia Eritroblástica Aguda , Co-Represor 1 de Receptor Nuclear , Humanos , Células K562 , Eritropoyesis/genética , Leucemia Eritroblástica Aguda/patología , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/genética , Co-Represor 1 de Receptor Nuclear/metabolismo , Co-Represor 1 de Receptor Nuclear/genética , Hemina/farmacología , Células Eritroides/metabolismo , Células Eritroides/citología , 5-Aminolevulinato Sintetasa/genética , 5-Aminolevulinato Sintetasa/metabolismo , Hemoglobinas/metabolismo , Técnicas de Silenciamiento del Gen , Péptidos y Proteínas de Señalización IntracelularAsunto(s)
Anemia de Fanconi , Leucemia Eritroblástica Aguda , Humanos , Anemia de Fanconi/genética , Anemia de Fanconi/complicaciones , Anemia de Fanconi/diagnóstico , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patología , Leucemia Eritroblástica Aguda/diagnóstico , Cariotipo Anormal , Masculino , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Niño , PreescolarRESUMEN
Fli-1, a member of the ETS family of transcription factors, was discovered in 1991 through retroviral insertional mutagenesis as a driver of mouse erythroleukemias. In the past 30 years, nearly 2000 papers have defined its biology and impact on normal development and cancer. In the hematopoietic system, Fli-1 controls self-renewal of stem cells and their differentiation into diverse mature blood cells. Fli-1 also controls endothelial survival and vasculogenesis, and high and low levels of Fli-1 are implicated in the auto-immune diseases systemic lupus erythematosus and systemic sclerosis, respectively. In addition, aberrant Fli-1 expression is observed in, and is essential for, the growth of multiple hematological malignancies and solid cancers. Here, we review the historical context and latest research on Fli-1, focusing on its role in hematopoiesis, immune response, and malignant transformation. The importance of identifying Fli-1 modulators (both agonists and antagonists) and their potential clinical applications is discussed.
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Leucemia Eritroblástica Aguda , Proteína Proto-Oncogénica c-fli-1 , Animales , Diferenciación Celular , Transformación Celular Neoplásica/genética , Hematopoyesis/genética , Leucemia Eritroblástica Aguda/patología , Ratones , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismoRESUMEN
OBJECTIVES: Glucose transporter 1 (GLUT1), a glucose transporter, is an abundant protein in erythrocytes with expression beginning early in erythropoiesis. We sought to evaluate the utility of GLUT1 immunohistochemistry (IHC) as a diagnostic marker for identifying erythroid differentiation in hematopoietic tissues, including neoplastic erythroid proliferations. METHODS: A variety of benign and neoplastic bone marrow biopsy specimens containing variable proportions of erythroid precursors were selected (nâ =â 46, including 36 cases of leukemia). GLUT1 IHC was performed using a commercially available polyclonal antibody. Each case was evaluated for staining of erythroid precursors, nonerythroid hematopoietic cells, and blasts. A GATA1/GLUT1 double stain was performed on one case to confirm coexpression of GLUT1 on early erythroid precursors. Staining was compared with other erythroid markers, including glycophorin C. RESULTS: GLUT1 demonstrated strong membranous staining in erythroid precursors of all cases, which was restricted largely to the erythroid lineage. Of the 36 leukemia cases, all 6 cases of pure erythroid leukemia and both cases of therapy-related acute myeloid leukemia with erythroid differentiation showed positive GLUT1 staining in blasts. Otherwise, only lymphoblasts in B-lymphoblastic leukemia showed weak to moderate granular cytoplasmic staining (four of five cases). CONCLUSIONS: GLUT1 IHC is a highly sensitive and relatively specific marker for erythroid lineage in benign and neoplastic bone marrow biopsy specimens.
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Médula Ósea , Transportador de Glucosa de Tipo 1 , Leucemia Eritroblástica Aguda , Biomarcadores/metabolismo , Médula Ósea/patología , Linaje de la Célula , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Inmunohistoquímica , Leucemia Eritroblástica Aguda/patologíaAsunto(s)
Leucemia Eritroblástica Aguda , Trombocitemia Esencial , Anciano , Femenino , Humanos , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patología , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/metabolismo , Trombocitemia Esencial/patologíaRESUMEN
NKL homeobox genes encode transcription factors that impact normal development and hematopoietic malignancies if deregulated. Recently, we established an NKL-code that describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL genes in leukemia/lymphoma. Here, we identify ectopic expression of NKL homeobox gene NKX2-4 in an erythroblastic acute myeloid leukemia (AML) cell line OCI-M2 and describe investigation of its activating factors and target genes. Comparative expression profiling data of AML cell lines revealed in OCI-M2 an aberrantly activated program for endothelial development including master factor ETV2 and the additional endothelial signature genes HEY1, IRF6, and SOX7. Corresponding siRNA-mediated knockdown experiments showed their role in activating NKX2-4 expression. Furthermore, the ETV2 locus at 19p13 was genomically amplified, possibly underlying its aberrant expression. Target gene analyses of NKX2-4 revealed activated ETV2, HEY1, and SIX5 and suppressed FLI1. Comparative expression profiling analysis of public datasets for AML patients and primary megakaryocyte-erythroid progenitor cells showed conspicuous similarities to NKX2-4 activating factors and the target genes we identified, supporting the clinical relevance of our findings and developmental disturbance by NKX2-4. Finally, identification and target gene analysis of aberrantly expressed NKX2-3 in AML patients and a megakaryoblastic AML cell line ELF-153 showed activation of FLI1, contrasting with OCI-M2. FLI1 encodes a master factor for myelopoiesis, driving megakaryocytic differentiation and suppressing erythroid differentiation, thus representing a basic developmental target of these homeo-oncogenes. Taken together, we have identified aberrantly activated NKL homeobox genes NKX2-3 and NKX2-4 in AML, deregulating genes involved in megakaryocytic and erythroid differentiation processes, and thereby contributing to the formation of specific AML subtypes.
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Células Eritroides/citología , Proteínas de Homeodominio/genética , Leucemia Eritroblástica Aguda/genética , Megacariocitos/citología , Factores de Transcripción/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Ciclo Celular/genética , Diferenciación Celular/genética , Línea Celular Tumoral , Endotelio/citología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Factores Reguladores del Interferón/genética , Leucemia Eritroblástica Aguda/patología , Interferencia de ARN , ARN Interferente Pequeño/genética , Factores de Transcripción SOXF/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
A series of heterocyclic compounds containing a spiro-fused pyrrolo[3,4-a]pyrrolizine and tryptanthrin framework have been synthesized and studied as potential antitumor agents. Cytotoxicity of products was screened against human erythroleukemia (K562) and human cervical carcinoma (HeLa) cell lines. Among the screened compounds. 4a, 4b and 5a were active against human erythroleukemia (K562) cell line, while 4a and 5a were active against cervical carcinoma (HeLa) cell line. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G2/M phase and induced apoptosis. Using confocal microscopy, we found that with 4a and 5a treatment of HeLa cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 76-91% of cells. We discovered that HeLa cells after treatment with compounds 4a and 5a significantly reduced the number of cells with filopodium-like membrane protrusions (from 63 % in control cells to 29% after treatment) and a decrease in cell motility.
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Antineoplásicos/farmacología , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Quinazolinas/farmacología , Compuestos de Espiro/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patología , Quinazolinas/síntesis química , Compuestos de Espiro/síntesis química , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
Precise control of gene expression during differentiation relies on the interplay of chromatin and nuclear structure. Despite an established contribution of nuclear membrane proteins to developmental gene regulation, little is known regarding the role of inner nuclear proteins. Here we demonstrate that loss of the nuclear scaffolding protein Matrin-3 (Matr3) in erythroid cells leads to morphological and gene expression changes characteristic of accelerated maturation, as well as broad alterations in chromatin organization similar to those accompanying differentiation. Matr3 protein interacts with CTCF and the cohesin complex, and its loss perturbs their occupancy at a subset of sites. Destabilization of CTCF and cohesin binding correlates with altered transcription and accelerated differentiation. This association is conserved in embryonic stem cells. Our findings indicate Matr3 negatively affects cell fate transitions and demonstrate that a critical inner nuclear protein impacts occupancy of architectural factors, culminating in broad effects on chromatin organization and cell differentiation.
Asunto(s)
Cromatina/química , Leucemia Eritroblástica Aguda/patología , Proteínas Asociadas a Matriz Nuclear/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Factor de Unión a CCCTC , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular/fisiología , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/ultraestructura , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Células Madre Embrionarias/fisiología , Células Eritroides/patología , Leucemia Eritroblástica Aguda/metabolismo , Ratones Noqueados , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas de Unión al ARN/genética , CohesinasRESUMEN
Among the eight human glutathione peroxidase isoforms, glutathione peroxidase 4 (GPX4) is the only enzyme capable of reducing complex lipid peroxides to the corresponding alcohols. In mice, corruption of the Gpx4 gene leads to embryonic lethality and more detailed expression silencing studies have implicated the enzyme in several physiological processes (e.g., embryonal cerebrogenesis, neuronal function, male fertility). Experiments with conditional knockout mice, in which expression of the Gpx4 gene was silenced in erythroid precursors, indicated a role of Gpx4 in erythropoiesis. To test this hypothesis in a cellular in vitro model we transfected mouse erythroleukemia cells with a Gpx4 siRNA construct and followed the expression kinetics of erythropoietic gene products. Our data indicate that Gpx4 is expressed at high levels in mouse erythroleukemia cells and that expression silencing of the Gpx4 gene delays in vitro erythropoiesis. However, heterozygous expression of a catalytically inactive Gpx4 mutant (Gpx4+/Sec46Ala) did not induce a defective erythropoietic phenotype in different in vivo and ex vivo models. These data suggest that Gpx4 plays a role in erythroid differentiation of mouse erythroleukemia cells but that heterozygous expression of a catalytically inactive Gpx4 is not sufficient to compromise in vivo and ex vivo erythropoiesis.
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Eritropoyesis , Leucemia Eritroblástica Aguda/patología , Mitocondrias/patología , Estrés Oxidativo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Animales , Leucemia Eritroblástica Aguda/etiología , Leucemia Eritroblástica Aguda/metabolismo , Masculino , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismoRESUMEN
Heme plays a critical role in catalyzing life-essential redox reactions in all cells, and its synthesis must be tightly balanced with cellular requirements. Heme synthesis in eukaryotes is tightly regulated by the mitochondrial AAA+ unfoldase CLPX (caseinolytic mitochondrial matrix peptidase chaperone subunit X), which promotes heme synthesis by activation of δ-aminolevulinate synthase (ALAS/Hem1) in yeast and regulates turnover of ALAS1 in human cells. However, the specific mechanisms by which CLPX regulates heme synthesis are unclear. In this study, we interrogated the mechanisms by which CLPX regulates heme synthesis in erythroid cells. Quantitation of enzyme activity and protein degradation showed that ALAS2 stability and activity were both increased in the absence of CLPX, suggesting that CLPX primarily regulates ALAS2 by control of its turnover, rather than its activation. However, we also showed that CLPX is required for PPOX (protoporphyrinogen IX oxidase) activity and maintenance of FECH (ferrochelatase) levels, which are the terminal enzymes in heme synthesis, likely accounting for the heme deficiency and porphyrin accumulation observed in Clpx-/- cells. Lastly, CLPX is required for iron utilization for hemoglobin synthesis during erythroid differentiation. Collectively, our data show that the role of CLPX in yeast ALAS/Hem1 activation is not conserved in vertebrates as vertebrates rely on CLPX to regulate ALAS turnover as well as PPOX and FECH activity. Our studies reveal that CLPX mutations may cause anemia and porphyria via dysregulation of ALAS, FECH, and PPOX activities, as well as of iron metabolism.
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5-Aminolevulinato Sintetasa/metabolismo , Endopeptidasa Clp/metabolismo , Ferroquelatasa/metabolismo , Hemo/biosíntesis , Hierro/metabolismo , Leucemia Eritroblástica Aguda/patología , Mitocondrias/metabolismo , Animales , Línea Celular Tumoral , Endopeptidasa Clp/genética , Activación Enzimática , Técnicas de Inactivación de Genes/métodos , Leucemia Eritroblástica Aguda/enzimología , Leucemia Eritroblástica Aguda/genética , Ratones , Modelos Animales , Proteolisis , Pez CebraRESUMEN
In recent years, adoptive cell therapy of immune effector cells, such as chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, and epitope-specific cytotoxic T lymphocyte (CTL) cells have been employed in clinical trials. In addition, CD19 CAR-T cells have been approved by the FDA for treatment of non-Hodgkin lymphoma and diffuse large B-cell lymphoma. In this context, it is vital to detect cellular cytotoxicity and monitor the quality of ex vivo expanded immune cells before product release and patient infusion. Target cells could proliferate in parallel with effector cells during the cytotoxicity assay, making it difficult to estimate the death ratio using conventional approaches. Meanwhile, non-specific dyes or non-homogeneous biomarkers for target cells may interfere with the final readout post addition of effector cells. Here, we modified a component of the coincubation medium to suppress the spontaneous release of bis(acetoxymethyl)2,2':6',2â³-terpyridine-6,6â³-dicarboxylate and sustained the window at a stable range (~70%). Further, the optimized Eu-TDA method presented reliable outcomes compared with lactate dehydrogenase detection and was compatible with cytotoxicity tests for NK cells and specific CTLs. Finally, the reported assay can accurately detect death of target cells depending on the amount of hydrophilic complex and can be reliably applied in quality control and cell activity evaluation tests on co-suspended effector and target cells. SUMMARY: A medium component for cellular coincubations (and associated protocols) have been optimized and validated for cytotoxicity assays, which can reliably evaluate the potency of engineered CD19 CAR-T cells, NK cells, and specific CTLs. In particular, the reported method can be applied widely in routine assays for bi-suspended effector and target cells with a stable window.
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Citotoxicidad Inmunológica , Inmunohistoquímica , Inmunoterapia Adoptiva , Células Asesinas Naturales/trasplante , Leucemia Eritroblástica Aguda/terapia , Linfocitos T Citotóxicos/trasplante , Antígenos CD19/genética , Antígenos CD19/inmunología , Supervivencia Celular , Técnicas de Cocultivo , Epítopos , Citometría de Flujo , Humanos , Células K562 , Células Asesinas Naturales/inmunología , Leucemia Eritroblástica Aguda/inmunología , Leucemia Eritroblástica Aguda/patología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T Citotóxicos/inmunologíaAsunto(s)
Trastornos de las Plaquetas Sanguíneas/patología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Leucemia Eritroblástica Aguda/patología , Leucemia Mieloide Aguda/patología , Mutación , Trastornos Mieloproliferativos/patología , Bioensayo , Trastornos de las Plaquetas Sanguíneas/genética , Trastornos de las Plaquetas Sanguíneas/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/clasificación , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Subunidad beta del Factor de Unión al Sitio Principal/genética , Predisposición Genética a la Enfermedad , Humanos , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Fosforilación , Activación TranscripcionalRESUMEN
Acute erythroid leukemia (AEL) is a rare and aggressive hematologic malignancy with no specific treatment. Sanguisorba officinalis L. (S. officinalis), a well-known traditional Chinese medicine, possesses potent anticancer activity. However, the active components of S. officinalis against AEL and the associated molecular mechanisms remain unknown. In this study, we predicted the anti-AML effect of S. officinalis based on network pharmacology. Through the identification of active components of S. officinalis, we found that 3,8-Di-O-methylellagic acid 2-O-glucoside (DMAG) not only significantly inhibited the proliferation of erythroleukemic cell line HEL, but also induced their differentiation to megakaryocytes. Furthermore, we demonstrated that DMAG could prolong the survival of AEL mice model. Whole-transcriptome sequencing was performed to elucidate the underlying molecular mechanisms associated with anti-AEL effect of DMAG. The results showed that the total of 68 miRNAs, 595 lncRNAs, 4030 mRNAs and 35 circRNAs were significantly differentially expressed during DMAG induced proliferation inhibition and differentiation of HEL cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed miRNAs, lncRNAs, mRNAs and circRNAs were mainly involved in metabolic, HIF-1, MAPK, Notch pathway and apoptosis. The co-expression networks showed that miR-23a-5p, miR-92a-1-5p, miR-146b and miR-760 regulatory networks were crucial for megakaryocyte differentiation induced by DMAG. In conclusion, our results suggest that DMAG, derived from S. officinalis might be a potent differentiation inducer of AEL cells and provide important information on the underlying mechanisms associated with its anti-AEL activity.