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1.
Genes Dev ; 32(5-6): 324-326, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29593065

RESUMEN

Hematopoietic stem cells (HSCs) reside and are maintained in specialized microenvironments within the bone marrow known as niches, which are comprised of various cell types. Among them, leptin receptor (LepR)-expressing CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells are known to create a niche for HSCs and at the same time to give rise to osteoblasts. These two functions of CAR/LepR+ cells appear to be tightly but inversely regulated to ensure adequate physical space for HSCs. However, how osteogenesis is prevented in CAR cells to maintain spaces available for HSCs and hematopoiesis remains unclear. In this issue of Genes & Development, Seike and colleagues (pp. 359-372) report that the transcription factor early B-cell factor (Ebf3) is preferentially expressed by CAR/LepR+ cells and inhibits CAR cell differentiation into osteoblasts while at the same time maintaining self-renewal of CAR/LepR+ cells. Using conditional knockout and retroviral systems, the investigators show that loss of Ebf3 in CAR cells impairs HSC numbers and leads to osteosclerosis. This study provides novel insights into transcriptional requirements for CAR cell bone formation by identifying Ebf3 as a niche factor secreted from CAR/Lepr+ cells that regulates the interplay between osteogenesis and hematopoiesis.


Asunto(s)
Osteogénesis , Nicho de Células Madre , Médula Ósea , Hematopoyesis , Células Madre Hematopoyéticas
2.
Biochim Biophys Acta ; 1863(3): 490-498, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26681532

RESUMEN

Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of ß-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of ß-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require ß-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of ß-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate ß-catenin signaling in osteoblasts. Consistent with a lack of ß-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of ß-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate ß-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.


Asunto(s)
Hematopoyesis , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Mutación , Osteoblastos/metabolismo , beta Catenina/metabolismo , Adulto , Anciano , Animales , Densidad Ósea/genética , Línea Celular , Línea Celular Tumoral , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones Noqueados , Persona de Mediana Edad , Osteogénesis/genética , Transducción de Señal/genética , Adulto Joven
3.
Blood ; 124(18): 2834-46, 2014 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-25139351

RESUMEN

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.


Asunto(s)
Progresión de la Enfermedad , Leucemia/patología , Osteoblastos/patología , Animales , Recuento de Células , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Leucemia/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Osteoblastos/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico
4.
J Clin Immunol ; 33(2): 368-77, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23097038

RESUMEN

The aim of this work was to study the expression and function of the innate immune receptor dectin-1 in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We studied twenty-six patients with SLE not receiving immunosuppressive therapy, twenty-six patients with RA, and fifteen controls. We found that monocytes from SLE patients showed a diminished expression of dectin-1 compared to healthy controls, and an inverse correlation between percent of dectin-1(+) cells and the disease activity score was detected. In addition, cells from SLE patients showed an abnormal calcium flux response induced by dectin-1 ligands as well as an enhanced release of IL-1ß, IL-6 and TNF-α, but not IL-23, upon dectin-1 engagement. Monocytes from patients with RA also showed a diminished expression, and a defective function of dectin-1. Our data suggest that dectin-1 receptor defects could contribute to the pathogenesis of autoimmune inflammatory conditions.


Asunto(s)
Artritis Reumatoide/metabolismo , Lectinas Tipo C/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Monocitos/metabolismo , Adulto , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Citocinas/biosíntesis , Femenino , Regulación de la Expresión Génica , Humanos , Inmunofenotipificación , Lectinas Tipo C/genética , Lupus Eritematoso Sistémico/genética , Masculino , Monocitos/inmunología , Adulto Joven
5.
Cancer Discov ; 12(4): 1106-1127, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35046097

RESUMEN

Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome resistance to targeted therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor 1B (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a proinflammatory state in osteoblasts that, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback loop on leukemia cells by increasing expression of IDO1-the rate-limiting enzyme for kynurenine synthesis-thereby enabling AML progression. This leukemia-osteoblast cross-talk, conferred by the kynurenine-HTR1B-SAA-IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment. SIGNIFICANCE: AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell nonautonomous progression mechanism that involves activation of a kynurenine-HTR1B-SAA-IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance. This article is highlighted in the In This Issue feature, p. 873.


Asunto(s)
Quinurenina , Leucemia Mieloide Aguda , Animales , Humanos , Quinurenina/metabolismo , Quinurenina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Osteoblastos/metabolismo , Transducción de Señal , Microambiente Tumoral
6.
Infect Immun ; 78(4): 1426-36, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20100861

RESUMEN

Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as beta-glucan seems to be a mechanism that fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall beta-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IkappaB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in beta-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target.


Asunto(s)
Candida albicans/inmunología , Candida albicans/fisiología , Proteínas Fúngicas/fisiología , Regulación Fúngica de la Expresión Génica , Proteínas de la Membrana/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Proteínas del Tejido Nervioso/metabolismo , beta-Glucanos/metabolismo , Candida albicans/genética , Adhesión Celular , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Proteínas Fúngicas/genética , Perfilación de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Lectinas Tipo C , Macrófagos/inmunología , Macrófagos/microbiología , Proteínas de la Membrana/inmunología , Viabilidad Microbiana , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteínas del Tejido Nervioso/inmunología , Fagocitosis , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Bazo/inmunología , beta-Glucanos/inmunología
7.
Cell Microbiol ; 11(8): 1179-89, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19416270

RESUMEN

Candida albicans is a major cause of oropharyngeal, vulvovaginal and haematogenously disseminated candidiasis. Endocytosis of C. albicans hyphae by host cells is a prerequisite for tissue invasion. This internalization involves interactions between the fungal invasin Als3 and host E- or N-cadherin. Als3 shares some structural similarity with InlA, a major invasion protein of the bacterium Listeria monocytogenes. InlA mediates entry of L. monocytogenes into host cells through binding to E-cadherin. A role in internalization, for a non-classical stimulation of the clathrin-dependent endocytosis machinery, was recently highlighted. Based on the similarities between the C. albicans and L. monocytogenes invasion proteins, we studied the role of clathrin in the internalization of C. albicans. Using live-cell imaging and indirect immunofluorescence of epithelial cells infected with C. albicans, we observed that host E-cadherin, clathrin, dynamin and cortactin accumulated at sites of C. albicans internalization. Similarly, in endothelial cells, host N-cadherin, clathrin and cortactin accumulated at sites of fungal endocytosis. Furthermore, clathrin, dynamin or cortactin depletion strongly inhibited C. albicans internalization by epithelial cells. Finally, beads coated with Als3 were internalized in a clathrin-dependent manner. These data indicate that C. albicans, like L. monocytogenes, hijacks the clathrin-dependent endocytic machinery to invade host cells.


Asunto(s)
Candida albicans/metabolismo , Candidiasis/metabolismo , Clatrina/metabolismo , Endocitosis , Interacciones Huésped-Patógeno , Cadherinas/metabolismo , Candida albicans/citología , Candida albicans/patogenicidad , Candidiasis/microbiología , Cortactina/metabolismo , Dinaminas/metabolismo , Células Epiteliales/metabolismo , Proteínas Fúngicas/metabolismo , Células HeLa , Humanos , Hifa/citología , Hifa/metabolismo , Microscopía Confocal , Virulencia
8.
Science ; 363(6431)2019 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-30846568

RESUMEN

Commensal bacteria influence host physiology, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB) are transferred into intestinal epithelial cells (IECs) through adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. This process transfers microbial cell wall-associated proteins, including an antigen that stimulates mucosal T helper 17 (TH17) cell differentiation, into the cytosol of IECs in a cell division control protein 42 homolog (CDC42)-dependent manner. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB and decreased epithelial antigen acquisition, with consequent loss of mucosal TH17 cells. Our findings demonstrate direct communication between a resident gut microbe and the host and show that under physiological conditions, IECs acquire antigens from commensal bacteria for generation of T cell responses to the resident microbiota.


Asunto(s)
Antígenos Bacterianos/inmunología , Endocitosis/inmunología , Microbioma Gastrointestinal/inmunología , Interacciones Microbiota-Huesped/inmunología , Mucosa Intestinal/inmunología , Linfocitos Intraepiteliales/inmunología , Células Th17/inmunología , Animales , Bacterias/inmunología , Endocitosis/genética , Homeostasis/genética , Activación de Linfocitos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Simbiosis , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/fisiología
9.
Artículo en Inglés | MEDLINE | ID: mdl-28963115

RESUMEN

Hematopoietic stem cells (HSCs) interact dynamically with an intricate network of cells in the bone marrow (BM) microenvironment or niche. These interactions provide instructive cues that influence the production and lineage determination of different types of blood cells and maintenance of HSC quiescence. They also contribute to hematopoietic deregulation and hematological myeloid malignancies. Alterations in the BM niche are commonly observed in myeloid malignancies and contribute to the aberrant function of myelodysplastic and leukemia-initiating stem cells. In this work, we review how different components of the BM niche affect normal hematopoiesis, the molecular signals that govern this interaction, and how genetic changes in stromal cells or alterations in remodeled malignant BM niches contribute to myeloid malignancies. Understanding the intricacies between normal and malignant niches and their modulation may provide insights into developing novel therapeutics for blood disorders.


Asunto(s)
Neoplasias de la Médula Ósea/patología , Médula Ósea/fisiología , Microambiente Celular/fisiología , Quimiocina CXCL12/metabolismo , Células Endoteliales/fisiología , Hematopoyesis/fisiología , Células Madre Hematopoyéticas , Humanos , Células Madre Mesenquimatosas/metabolismo , Nestina/metabolismo , Neuroglía/fisiología , Neuronas/fisiología , Osteoblastos/fisiología , Osteocitos/fisiología , Receptores de Leptina/metabolismo , Nicho de Células Madre/fisiología , Sistema Nervioso Simpático/fisiología
10.
Curr Mol Biol Rep ; 3(2): 53-62, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29098141

RESUMEN

PURPOSE OF REVIEW: This review focuses on evidence highlighting the bidirectional crosstalk between the hematopoietic stem cell (HSC) and their surrounding stromal cells, with a particular emphasis on cells of the osteoblast lineage. The role and molecular functions of osteoblasts in normal hematopoiesis and in myeloid hematological malignancies is discussed. RECENT FINDINGS: Cells of the osteoblast lineage have emerged as potent regulators of HSC expansion that regulate their recruitment and, depending on their stage of differentiation, their activity, proliferation and differentiation along the lymphoid, myeloid and erythroid lineages. In addition, mutations in mature osteoblasts or their progenitors induce myeloid malignancies. Conversely, signals from myelodysplastic cells can remodel the osteoblastic niche to favor self-perpetuation. SUMMARY: Understanding cellular crosstalk between osteoblastic cells and HSCs in the bone marrow microenvironment is of fundamental importance for developing therapies against benign and malignant hematological diseases.

11.
Cell Metab ; 23(6): 1078-1092, 2016 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-27304508

RESUMEN

Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.


Asunto(s)
Adaptación Fisiológica , Fibras Musculares Esqueléticas/metabolismo , Osteocalcina/metabolismo , Condicionamiento Físico Animal , Transducción de Señal , Envejecimiento/metabolismo , Animales , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Modelos Biológicos
12.
J Immunol Methods ; 421: 104-111, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25858227

RESUMEN

Segmented filamentous bacteria (SFB) are Gram-positive, anaerobic, spore-forming commensals that reside in the gut of many animal species. Described more than forty years ago, SFB have recently gained interest due to their unique ability to modulate the host immune system through induction of IgA and Th17 cells. Here, we describe a collection of methods to detect and quantify SFB and SFB adhesion in intestinal mucosa, as well as SFB-specific CD4 T cells in the lamina propria. In addition, we describe methods for purification of SFB from fecal material of SFB-monoassociated gnotobiotic mice. Using these methods we examine the kinetics of SFB colonization and Th17 cell induction. We also show that SFB colonize unevenly the intestinal mucosa and that SFB adherence occurs predominantly in the terminal ileum and correlates with an increased proportion of SFB-specific Th17 cells.


Asunto(s)
Infecciones por Bacterias Grampositivas/inmunología , Bacterias Grampositivas Formadoras de Endosporas/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Células Th17/inmunología , Animales , Adhesión Bacteriana/inmunología , Heces/microbiología , Ratones , Ratones Endogámicos C57BL , Microbiota/inmunología , Simbiosis
13.
Cell Host Microbe ; 15(5): 611-22, 2014 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-24832455

RESUMEN

Dendritic cells (DCs) phagocytose, process, and present bacterial antigens to T lymphocytes to trigger adaptive immunity. In vivo, bacteria can also be found inside T lymphocytes. However, T cells are refractory to direct bacterial infection, leaving the mechanisms by which bacteria invade T cells unclear. We show that T cells take up bacteria from infected DCs by the process of transinfection, which requires direct contact between the two cells and is enhanced by antigen recognition. Prior to transfer, bacteria localize to the immunological synapse, an intimate DC/T cell contact structure that activates T cells. Strikingly, T cells efficiently eliminate the transinfecting bacteria within the first hours after infection. Transinfected T cells produced high levels of proinflammatory cytokines and were able to protect mice from bacterial challenge following adoptive transfer. Thus, T lymphocytes can capture and kill bacteria in a manner reminiscent of innate immunity.


Asunto(s)
Infecciones Bacterianas/microbiología , Células Dendríticas/inmunología , Listeria monocytogenes/inmunología , Salmonella enterica/inmunología , Staphylococcus aureus/inmunología , Linfocitos T/inmunología , Animales , Células Cultivadas , Citocinas/inmunología , Células Dendríticas/microbiología , Femenino , Humanos , Inmunidad Innata , Masculino , Ratones , Ratones Endogámicos C57BL , Fagocitosis , Linfocitos T/microbiología
14.
PLoS One ; 7(2): e32451, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22384256

RESUMEN

Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2 in vivo. Together these findings suggest that adult and pediatric patients with BCR-ABL-negative leukemia and JAK2 overexpression may benefit from targeted therapies.


Asunto(s)
Janus Quinasa 2/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-bcr/metabolismo , Animales , Apoptosis , Línea Celular , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Fosforilación , Estructura Terciaria de Proteína , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Proteína bcl-X/metabolismo
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