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1.
Leukemia ; 29(8): 1741-53, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25778099

RESUMEN

Notch signaling is essential for definitive hematopoiesis, but its role in human embryonic hematopoiesis is largely unknown. We show that in hESCs the expression of the Notch ligand DLL4 is induced during hematopoietic differentiation. We found that DLL4 is only expressed in a sub-population of bipotent hematoendothelial progenitors (HEPs) and segregates their hematopoietic versus endothelial potential. We demonstrate at the clonal level and through transcriptome analyses that DLL4(high) HEPs are enriched in endothelial potential, whereas DLL4(low/-) HEPs are committed to the hematopoietic lineage, albeit both populations still contain bipotent cells. Moreover, DLL4 stimulation enhances hematopoietic differentiation of HEPs and increases the amount of clonogenic hematopoietic progenitors. Confocal microscopy analysis of whole differentiating embryoid bodies revealed that DLL4(high) HEPs are located close to DLL4(low/-) HEPs, and at the base of clusters of CD45+ cells, resembling intra-aortic hematopoietic clusters found in mouse embryos. We propose a model for human embryonic hematopoiesis in which DLL4(low/-) cells within hemogenic endothelium receive Notch-activating signals from DLL4(high) cells, resulting in an endothelial-to-hematopoietic transition and their differentiation into CD45+ hematopoietic cells.


Asunto(s)
Biomarcadores/metabolismo , Diferenciación Celular , Células Madre Embrionarias/citología , Endotelio/citología , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/citología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Cuerpos Embrioides , Células Madre Embrionarias/metabolismo , Endotelio/metabolismo , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Humanos , Técnicas para Inmunoenzimas , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
2.
Leukemia ; 28(3): 666-74, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24240202

RESUMEN

MLL-AF4 fusion is hallmark in high-risk infant pro-B-acute lymphoblastic leukemia (pro-B-ALL). Our limited understanding of MLL-AF4-mediated transformation reflects the absence of human models reproducing this leukemia. Hematopoietic stem/progenitor cells (HSPCs) constitute likely targets for transformation. We previously reported that MLL-AF4 enhanced hematopoietic engraftment and clonogenic potential in cord blood (CB)-derived CD34+ HSPCs but was not sufficient for leukemogenesis, suggesting that additional oncogenic lesions are required for MLL-AF4-mediated transformation. MLL-AF4+ pro-B-ALL display enormous levels of FLT3, and occasionally FLT3-activating mutations, thus representing a candidate cooperating event in MLL-AF4+ pro-B-ALL. We have explored whether FLT3.TKD (tyrosine kinase domain) mutation or increased expression of FLT3.WT (wild type) cooperates with MLL-AF4 to immortalize/transform CB-CD34+ HSPCs. In vivo, FLT3.TKD/FLT3.WT alone, or in combination with MLL-AF4, enhances hematopoietic repopulating function of CB-CD34+ HSPCs without impairing migration or hematopoietic differentiation. None of the animals transplanted with MLL-AF4+FLT3.TKD/WT-CD34+ HSPCs showed any sign of disease after 16 weeks. In vitro, enforced expression of FLT3.TKD/FLT3.WT conveys a transient overexpansion of MLL-AF4-expressing CD34+ HSPCs associated to higher proportion of cycling cells coupled to lower apoptotic levels, but does not augment clonogenic potential nor confer stable replating. Together, FLT3 activation does not suffice to immortalize/transform MLL-AF4-expressing CB-CD34+ HSPCs, suggesting the need of alternative (epi)-genetic cooperating oncogenic lesions.


Asunto(s)
Antígenos CD34/inmunología , Proteínas de Unión al ADN/metabolismo , Sangre Fetal/inmunología , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas Nucleares/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismo , Animales , Transformación Celular Neoplásica , Técnicas de Cocultivo , N-Metiltransferasa de Histona-Lisina , Humanos , Ligandos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Factores de Elongación Transcripcional
3.
Leukemia ; 23(8): 1374-7, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19357700

RESUMEN

Inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). However, GSIs seem to have limited antileukemic activity in human T-ALL and are associated with severe gastrointestinal toxicity resulting from inhibition of NOTCH signaling in the gut. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity. Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glucocorticoides/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Receptor Notch1/antagonistas & inhibidores , Adulto , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Niño , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/prevención & control , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucocorticoides/administración & dosificación , Proteínas de Homeodominio/fisiología , Humanos , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/fisiología , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , Procesamiento Proteico-Postraduccional , Receptor Notch1/genética , Factor de Transcripción HES-1
4.
Leukemia ; 20(7): 1279-87, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16688224

RESUMEN

Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to gamma-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Línea Celular Tumoral/citología , Reordenamiento Génico de Linfocito T/genética , Leucemia-Linfoma de Células T del Adulto/patología , Receptor Notch1/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Diferenciación Celular , Línea Celular Tumoral/fisiología , Niño , Cromosomas Humanos Par 7 , Cromosomas Humanos Par 9 , Inhibidores Enzimáticos/farmacología , Regulación Leucémica de la Expresión Génica , Genes Supresores de Tumor/fisiología , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Receptor Notch1/metabolismo , Transducción de Señal , Translocación Genética
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