RESUMEN
Here, we report a unique acute myeloid leukemia (AML) bone marrow-derived mesenchymal stem cell (MSC) with both mesenchymal and endothelial potential, which we have named Mesenchymal Cancer Stem Cells (MCSCs). These MCSCs are CD90-CD13-CD44+ and differ from MSCs in isolation, expansion, differentiation, immunophenotype, and cytokine release profile. Furthermore, blocking CD44 inhibited the proliferation and cluster formation of early MCSCs with lower ICAM-1 protein levels. Similar CD90-CD44+ cancer stem cells have been reported in both gastric and breast cancers, which grew in floating spheres in vitro and exhibited mesenchymal features and high metastatic/tumorigenic capabilities in vivo. Our novel discovery provides the first evidence that certain AMLs may be comprised of both hematopoietic and stromal malignant cells. Targeting MCSCs and their cytokine release has potential as a novel therapeutic approach in AML.
Asunto(s)
Antígenos de Neoplasias/análisis , Médula Ósea/patología , Receptores de Hialuranos/análisis , Leucemia Mielomonocítica Aguda/patología , Células Madre Mesenquimatosas/patología , Células Madre Neoplásicas/patología , Proteínas Angiogénicas/metabolismo , Adhesión Celular , Separación Celular , Citocinas/metabolismo , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leucemia Mielomonocítica Aguda/metabolismo , Células Madre Mesenquimatosas/química , Células Madre Mesenquimatosas/metabolismo , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/química , Células Madre Neoplásicas/clasificación , Células Madre Neoplásicas/metabolismo , Células Tumorales CultivadasRESUMEN
We present a rare case of leukemia cutis presenting with an ulcer on the ventral penis. A 60-year-old Chinese man was referred for a penile ulcer of 10 days. He was diagnosed with acute myelomonocytic leukemia 6 months earlier and had received 2 cycles of venetoclax with azacitidine. He developed a spontaneous penile blister. It ulcerated after the patient pricked it with a needle. This enlarged after traditional medicated ointment was applied. He denied pain, itch, urethral discharge, systemic symptoms, or rashes elsewhere.
Asunto(s)
Leucemia Mielomonocítica Aguda/patología , Pene/patología , Neoplasias Cutáneas/patología , Humanos , Masculino , Persona de Mediana Edad , Úlcera/etiología , Úlcera/patologíaAsunto(s)
Leucemia Mielomonocítica Aguda/patología , Monocitos/patología , Cariotipo Anormal , Anciano de 80 o más Años , Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Diagnóstico Diferencial , Resultado Fatal , Femenino , Citometría de Flujo , Genes p53 , Humanos , Leucemia Mielomonocítica Aguda/complicaciones , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/genética , Linfoma no Hodgkin/diagnóstico , Pancitopenia/etiologíaAsunto(s)
Isocitrato Deshidrogenasa/genética , Leucemia Mielomonocítica Aguda/genética , Mutación Missense , Proteínas de Neoplasias/genética , Regresión Neoplásica Espontánea , Mutación Puntual , Cariotipo Anormal , Alelos , Médula Ósea/patología , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 1/ultraestructura , Células Clonales , Resultado Fatal , Femenino , Humanos , Leucemia Mielomonocítica Aguda/complicaciones , Leucemia Mielomonocítica Aguda/patología , Linfohistiocitosis Hemofagocítica/etiología , Persona de Mediana EdadRESUMEN
Defined as a rare extramedullary tumor, myeloid sarcoma (MS) is in the attention of specialists, although the information in the literature is represented especially through case reports. MS can precede acute myeloid leukemia (AML), appear simultaneous and can be the only manifestation of leukemia relapse after allogeneic stem cell transplantation (allo-SCT). We present the case of a 30-year-old female diagnosed with acute myelomonocytic leukemia (AML M4), with complete remission (CR) after chemotherapy, followed by allo-SCT for consolidation. After five months, the patient presented right breast tumors. Ultrasound-guided biopsy of the breast lesion displayed diffuse infiltration of undifferentiated tumor cells, with blastic granulocytic features, strongly immunopositive for cluster of differentiation (CD) 45, CD99, CD34 and myeloperoxidase (MPO) and negative for all epithelial markers [MNF116, cytokeratin 7 (CK7), estrogen receptor (ER), progesterone receptor (PR), E-cadherin]. The final diagnosis was AML relapse with breast MS. After multiple leukemia relapses with breast MS, the patient died with cerebral bleeding secondary to severe thrombocytopenia.
Asunto(s)
Neoplasias de la Mama/etiología , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mielomonocítica Aguda/complicaciones , Sarcoma Mieloide/complicaciones , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adulto , Neoplasias de la Mama/patología , Femenino , Humanos , Leucemia Mielomonocítica Aguda/patologíaRESUMEN
Exosomes are virus-size membrane-bound vesicles of endocytic origin present in all body fluids. Plasma of AML patients is significantly enriched in exosomes, which carry a cargo of immunosuppressive molecules and deliver them to recipient immune cells, suppressing their functions. However, whether these exosomes originate from leukemic blasts or from various normal cells in the bone marrow or other tissues is unknown. In the current study, we developed an AML PDX model in mice and studied the molecular cargo and immune cell effects of the AML PDX exosomes in parallel with the exosomes from plasma of the corresponding AML patients. Fully engrafted AML PDX mice produced exosomes with characteristics similar to those of exosomes isolated from plasma of the AML patients who had donated the cells for engraftment. The engrafted leukemic cells produced exosomes that carried human proteins and leukemia-associated antigens, confirming the human origin of these exosomes. Furthermore, the AML-derived exosomes carried immunosuppressive proteins responsible for immune cell dysfunctions. Our studies of exosomes in AML PDX mice serve as a proof of concept that AML blasts are the source of immunosuppressive exosomes with a molecular profile that mimics the content and functions of the parental cells.
Asunto(s)
Exosomas , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/metabolismo , Escape del Tumor/fisiología , Anciano , Animales , Antígenos de Neoplasias/sangre , Femenino , Xenoinjertos , Humanos , Leucemia Mielomonocítica Aguda/patología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Trasplante de Neoplasias , Subgrupos de Linfocitos T/inmunologíaRESUMEN
BACKGROUND/AIM: Acute myeloid leukemia is well characterized by chromosomal aberrations that correspond to various subtypes of acute leukemias. The t(8;21)(q22;q22) is a frequent chromosomal abnormality strongly associated with acute myeloblastic leukemia with maturation (AML-M2), but is rarely associated with other subtypes. Translocation involving a third chromosome could produce new genetic rearrangements that lead to leukemogenesis. PATIENTS AND METHODS: Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) were performed to identify the karyotype. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the AML1/ETO transcript. RESULTS/CONCLUSION: We herein report a novel rearrangement with a three-way translocation involving chromosomes 8, 21 and another unknown chromosome, in an 83-year-old female patient diagnosed as AML-M4, with an ALM1/ETO negative transcript. This is an uncommon case of AML-M4 with three-way translocation in a new variant of t(8;21) acute myeloid leukaemia. The detailed mechanism of different phenotype expression is unclear. Further study is needed to identify the leukemogenetic transformation resulting from t(8;21) translocation.
Asunto(s)
Análisis Citogenético , Cariotipo , Leucemia Mielomonocítica Aguda/genética , Translocación Genética/genética , Anciano de 80 o más Años , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Femenino , Humanos , Hibridación Fluorescente in Situ/métodos , Cariotipificación/métodos , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/patologíaRESUMEN
A 19-year-old woman presented to the outpatient department with occasional ocular pain and redness and a perilimbal mass, which she noticed 5 months ago in her left eye. She had no systemic complaints. Ultrasound biomicroscopy of the mass showed a hypoechoic lesion with uniform reflectivity. The patient underwent an excision biopsy and a histopathological analysis revealed features suggestive of a granulocytic sarcoma/myeloid sarcoma. Further haematopathological evaluation confirmed concurrent acute myeloid (myelomonocytic) leukaemia French American British classification M4. There was complete remission of the ocular surface lesion and leukaemia with systemic chemotherapy. At the last follow-up of 18 months post-treatment the patient is free of disease.
Asunto(s)
Dolor Ocular/diagnóstico , Sarcoma Mieloide/patología , Sarcoma Mieloide/cirugía , Cuidados Posteriores , Biopsia , Quimioterapia/métodos , Dolor Ocular/etiología , Dolor Ocular/patología , Femenino , Humanos , Leucemia Mielomonocítica Aguda/patología , Microscopía Acústica/métodos , Inducción de Remisión , Sarcoma Mieloide/diagnóstico por imagen , Sarcoma Mieloide/tratamiento farmacológico , Resultado del Tratamiento , Adulto JovenRESUMEN
Acute myeloid leukaemia (AML) is a genetically heterogeneous, severe and rapidly progressing disease triggered by blocking granulocyte or monocyte differentiation and maturation. Overexpression of myeloid cell leukaemia-1 (Mcl-1) and Survivin is associated with drug resistance, tumour progression and inhibition of apoptotic mechanisms in leukaemia and several cancers. In the present study, we examined the combined effect of etoposide and dual siRNA-mediated silencing of Mcl-1 and Survivin on U-937 AML cells. The AML cells were co-transfected with Mcl-1 and Survivin-specific siRNAs and genes silencing were confirmed by quantitative real-time PCR and Western blotting. Subsequently, MTT assay was used for the evaluation of cytotoxic effects by dual siRNA and etoposide on their own and in combination. For the studying of apoptosis, DNA-histone ELISA and annexin-V/FITC assays were performed. Co-transfection of Mcl-1 and Survivin siRNA significantly blocked their expression at the mRNA and protein levels, leading to the induction of apoptosis and strong inhibition of growth (p < .05). Besides, combined treatment of etoposide with Mcl-1 and Survivin siRNAs co-transfection leads to synergistically enhance etoposide-induced cytotoxic and apoptotic effects (p < .05). The results showed that Mcl-1 and Survivin play a major role in the U937 cells survival and their resistance relative to etoposide. Thus, Mcl-1 and Survivin can be considered as promising molecular targets for the treatment of AML. The combination treatment with etoposide, and siRNA-mediated silencing of corresponding genes may be a novel strategy in chemoresistance AML treatment.
Asunto(s)
Apoptosis , Resistencia a Antineoplásicos , Etopósido/farmacología , Silenciador del Gen , Leucemia Mielomonocítica Aguda/terapia , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , ARN Interferente Pequeño/farmacología , Survivin/antagonistas & inhibidores , Humanos , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/biosíntesis , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , ARN Interferente Pequeño/genética , Survivin/biosíntesis , Survivin/genética , Células U937Asunto(s)
Leucemia Mielomonocítica Aguda/patología , Infiltración Leucémica/patología , Piel/patología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Diagnóstico Tardío , Etopósido/administración & dosificación , Resultado Fatal , Fatiga/etiología , Femenino , Fiebre/etiología , Humanos , Hidroxiurea/administración & dosificación , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/tratamiento farmacológico , Leucocitosis/etiología , Metrorragia/etiología , Metrorragia/cirugía , Persona de Mediana Edad , Mioma/complicaciones , Neoplasias Primarias Múltiples , Cuidados Paliativos , Neoplasias Uterinas/complicacionesAsunto(s)
Diferenciación Celular/genética , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/patología , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Médula Ósea/patología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Preescolar , Humanos , Inmunofenotipificación , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/tratamiento farmacológico , Masculino , Clasificación del Tumor , Nucleofosmina , Proteínas de Fusión Oncogénica/metabolismo , Resultado del TratamientoAsunto(s)
Adenoma/diagnóstico por imagen , Leucemia Mielomonocítica Aguda/complicaciones , Leucemia Mielomonocítica Aguda/diagnóstico , Melena/etiología , Neoplasias del Colon Sigmoide/diagnóstico por imagen , Adenoma/complicaciones , Adenoma/patología , Colonoscopía , Humanos , Leucemia Mielomonocítica Aguda/patología , Masculino , Persona de Mediana Edad , Recto , Neoplasias del Colon Sigmoide/complicaciones , Neoplasias del Colon Sigmoide/patología , Trombocitopenia/etiologíaRESUMEN
Patients with relapsed acute myeloid leukemia (AML) have limited therapeutic options. Vesicular stomatitis virus (VSV)-interferon ß (IFNß)-sodium iodide symporter (NIS) is an oncolytic VSV encoding IFNß and the NIS reporter. Syngeneic AML C1498 tumors responded to IV therapy with VSV-murine IFNß (mIFNß)-NIS in a dose-dependent manner. Imaging for NIS expression showed robust virus infection within the tumors. Virus infection did not increase programmed death ligand 1 (PD-L1) on tumor cells. Combining VSV-mIFNß-NIS with anti-PD-L1 antibody (Ab) therapy enhanced antitumor activity compared with treatment with virus alone or Ab alone; this enhancement was not significant at higher VSV-mIFNß-NIS doses. Systemic VSV therapy reduced systemic C1498-green fluorescent protein (GFP) tumor burden in the blood, bone marrow, spleen, and liver of mice with AML. Combination VSV-mIFNß-NIS and anti-PD-L1 Ab therapy significantly enhanced the survival of these mice with no evidence of toxicity, compared with isotype control, anti-PD-L1, or virus alone. There was an increase in tumor-infiltrating CD4 and CD8 cells. Single-agent VSV-mIFNß-NIS virotherapy induced both VSV-specific and GFP-specific CD8 T cells as determined by IFN-γ enzyme-linked immunospot, pentamer, and intracellular IFN-γ staining assays. Both of these responses were further enhanced by addition of anti-PD-L1 Ab. Depletion of CD8 or natural killer cells, but not CD4 cells, resulted in loss of antitumor activity in the VSV/anti-PD-L1 group. Clinical samples from chronic myelomonocytic leukemia and acute myelomonocytic leukemia appear to be especially susceptible to VSV. Overall, our studies show that oncolytic virotherapy combined with immune checkpoint blockade is a promising approach to AML therapy.
Asunto(s)
Antígeno B7-H1/inmunología , Inmunoterapia , Leucemia Mieloide Aguda/terapia , Viroterapia Oncolítica , Virus de la Estomatitis Vesicular Indiana/fisiología , Animales , Antígeno B7-H1/análisis , Médula Ósea/patología , Línea Celular Tumoral , Terapia Combinada , Femenino , Genes Reporteros , Vectores Genéticos/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Interferón beta/genética , Lentivirus/genética , Leucemia Mieloide Aguda/diagnóstico por imagen , Leucemia Mielomonocítica Aguda/patología , Leucemia Mielomonocítica Crónica/patología , Leucocitos Mononucleares/patología , Subgrupos Linfocitarios/inmunología , Linfocitos Infiltrantes de Tumor/química , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Proteínas de Neoplasias/análisis , Cintigrafía , Simportadores/genética , Carga TumoralRESUMEN
The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16;21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16;21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.
Asunto(s)
Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 21/genética , Regulación Neoplásica de la Expresión Génica/genética , Hematopoyesis/fisiología , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Proteínas de Neoplasias/fisiología , Proteínas de Fusión Oncogénica/fisiología , Proteína FUS de Unión a ARN/fisiología , Transducción de Señal/fisiología , Translocación Genética , Tretinoina/fisiología , Secuencias de Aminoácidos , Línea Celular Tumoral , Cromosomas Humanos Par 16/ultraestructura , Cromosomas Humanos Par 21/ultraestructura , Dimerización , Elementos de Facilitación Genéticos , Células Madre Hematopoyéticas/patología , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/fisiopatología , Leucemia Mielomonocítica Aguda/patología , Leucemia Mielomonocítica Aguda/fisiopatología , Complejos Multiproteicos , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/patología , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Regiones Promotoras Genéticas , Unión Proteica , Mapeo de Interacción de Proteínas , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteína FUS de Unión a ARN/antagonistas & inhibidores , Proteína FUS de Unión a ARN/genética , Receptores de Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Receptores X Retinoide/metabolismo , Transducción de Señal/efectos de los fármacos , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Tretinoina/farmacología , Células U937RESUMEN
Tumor protein p53 encoded by the TP53 gene in humans is known as a cancer biomarker in patients diagnosed with cancer, and it plays an essential role in apoptosis, genomic stability, and inhibition of angiogenesis. Cancer therapies with common chemotherapy methods are effective, as known, but have some side effects. Berberis vulgaris is traditionally administrated as a cancer drug. The current research aims to evaluate p53 as a biomarker in WEHI-3 cell line and to demonstrate the Berberis vulgaris fruit crude extract (BVFCE) as a new anticancer drug. For this purpose, we evaluated the effect of BVFCE in different concentrations against WEHI-3cell line in vitro and determined the quantitative level of p53 gene in the treated WEHI-3 cells. The results demonstrated that even at only 1 mg/ml concentration of Berberis vulgaris crude extract, there was a low level of p53 biomarker expression on WEHI-3 cells in comparison with doxorubicin. Therefore, the current study suggests BVFCE as a reliable anti-leukaemic drug and candidate for anticancer therapy. However, further investigation need be carried out to confirm its efficiency in vivo.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Berberis/química , Frutas/química , Leucemia Experimental/patología , Leucemia Mielomonocítica Aguda/patología , Fitoterapia , Extractos Vegetales/farmacología , Células 3T3 , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Genes p53 , Concentración 50 Inhibidora , Ratones , Proteína p53 Supresora de Tumor/análisisRESUMEN
Adenosine monophosphate-activated protein kinase (AMPK) is a sensor for cellular energy status. When the cellular energy level is decreased, AMPK is activated and functions to suppress energy-consuming processes, including protein synthesis. Recently, AMPK has received attention as an attractive molecular target for cancer therapy. Several studies have revealed that the activation of AMPK by chemical stimulators, such as metformin, induces apoptosis in a variety of hematologic malignant cells. From another perspective, these results suggest that the function of AMPK is impaired in hematologic tumor cells. However, the precise mechanisms by which this impairment occurs are not well understood. In melanoma cells, oncogenic BRAF constitutively activates the extracellular signal-regulated kinase (ERK) pathway and phosphorylates liver kinase B1, an upstream activator of 5' adenosine monophosphate-activated protein kinase (AMPK), resulting in the inactivation of liver kinase B1 and AMPK. In this study, we analyzed whether ERK is involved in the suppression of AMPK activity using established and primary human leukemia cells. We found an inverse correlation between the intensity of ERK activity and the degree of AMPK activation after stimulation with either glucose deprivation or metformin. We also found that the inhibition of ERK activity by U0126 restored AMPK activation after metformin treatment. Furthermore, a combined treatment with metformin and U0126 enhanced the antileukemic activity of metformin. Importantly, metformin induced ERK activation by suppressing the protein levels of dual specificity phosphatase 6, a negative regulator of ERK. This crosstalk between AMPK and ERK could diminish the antileukemic activity of metformin. Taken together, our present observations suggest a novel therapeutic strategy for improving the efficacy of metformin in treating leukemia.
Asunto(s)
Proteínas Quinasas Activadas por AMP/fisiología , Leucemia Mieloide Aguda/patología , Sistema de Señalización de MAP Quinasas/fisiología , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Proteínas de Neoplasias/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP/genética , Adulto , Anciano , Antineoplásicos/farmacología , Apoptosis , Butadienos/farmacología , Línea Celular Tumoral , Interacciones Farmacológicas , Fosfatasa 6 de Especificidad Dual/fisiología , Activación Enzimática , Retroalimentación Fisiológica , Femenino , Glucosa/farmacología , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mielomonocítica Aguda/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metformina/farmacología , Persona de Mediana Edad , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Células Tumorales CultivadasRESUMEN
We present a system-wide transcriptional network structure that controls cell types in the context of expression pattern transitions that correspond to cell type transitions. Co-expression based analyses uncovered a system-wide, ladder-like transcription factor cluster structure composed of nearly 1,600 transcription factors in a human transcriptional network. Computer simulations based on a transcriptional regulatory model deduced from the system-wide, ladder-like transcription factor cluster structure reproduced expression pattern transitions when human THP-1 myelomonocytic leukaemia cells cease proliferation and differentiate under phorbol myristate acetate stimulation. The behaviour of MYC, a reprogramming Yamanaka factor that was suggested to be essential for induced pluripotent stem cells during dedifferentiation, could be interpreted based on the transcriptional regulation predicted by the system-wide, ladder-like transcription factor cluster structure. This study introduces a novel system-wide structure to transcriptional networks that provides new insights into network topology.