RESUMEN

Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory ß subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.

Asunto(s)

Quinasa de la Caseína II/metabolismo , Leucemia Mieloide Aguda/metabolismo , FN-kappa B/metabolismo , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Adenosina Trifosfato/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Biomarcadores , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/genética , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Expresión Génica , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal

Asunto(s)

Células de la Médula Ósea/citología , Quinasa de la Caseína II/metabolismo , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/metabolismo , Osteoclastos/citología , Antineoplásicos/química , Supervivencia Celular , Citocinas/metabolismo , Silenciador del Gen , Humanos , Interleucina-6/metabolismo , Osteoblastos/citología , Fosforilación , Receptores CXCR4/metabolismo , Células del Estroma/citología , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

CK2 is a multitask kinase whose role is essential for a countless number of cellular processes, many of which are critical for blood cell development. A prevailing task for this kinase rests on counteracting programmed cell death triggered by multiple stimuli. CK2 is overexpressed in many solid tumors and in vivo mouse models have proven its tumorigenic potential. Recent data have suggested that CK2 may also have a significant role in the pathogenesis of hematopoietic tumors, such as multiple myeloma, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia and chronic myeloproliferative neoplasms. CK2 regulates hematopoiesis-associated signaling pathways and seems to reinforce biochemical cascades indispensable for tumor growth, proliferation and resistance to conventional and novel cytotoxic agents. Although its activity is multifold, recent evidence supports the rationale of CK2 inhibition as a therapeutic strategy in solid and hematological tumors and phase-I clinical trials are in progress to test the efficacy of this innovative therapeutic approach. In this review, we will summarize the data supporting CK2 as an oncogenic kinase in blood tumors and we will describe some critical signaling pathways, whose regulation by this protein kinase may be implicated in tumorigenesis.

Asunto(s)

Quinasa de la Caseína II/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias Hematológicas/etiología , Neoplasias Hematológicas/patología , Oncogenes/fisiología , Transducción de Señal , Animales , Supervivencia Celular , Neoplasias Hematológicas/enzimología , Humanos , Ratones

RESUMEN

Hemorrhoidal disease is a frequent cause of morbidity among the general population with a reported incidence of 4.4%, but little is known about its incidence and clinical features in kidney transplant recipients. Among 116 patients who had undergone kidney transplantation and were evaluated for hemorrhoidal disease, 82 had no hemorrhoids (70.6%), 28 (24%) had grade I hemorrhoids, and 6 (5.4%) had grade II hemorrhoids at the pretransplantation evaluation. Twenty-seven out of 116 recipients (22.4%) developed grade III or IV hemorrhoids after transplantation and underwent surgery. Hemorrhoidal disease was more frequent in patients with a pretransplantation history of hemorrhoids, with a rapid weight increase in the posttransplantation period, or who were aged between 30 and 50 years. Immunosuppressive therapy may play an important role in the worsening of hemorrhoidal disease among kidney transplant recipients. A prompt diagnosis and surgical treatment, whenever necessary, is mandatory for patients with clinical signs of worsening of hemorrhoids.

Asunto(s)

Hemorroides/epidemiología , Trasplante de Riñón/efectos adversos , Adulto , Anciano , Femenino , Hemorroides/clasificación , Hemorroides/cirugía , Humanos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/cirugía , Trasplante de Riñón/inmunología , Masculino , Persona de Mediana Edad , Várices/epidemiología , Aumento de Peso

Asunto(s)

Endocardio/patología , Neoplasias Cardíacas/patología , Leucemia Prolinfocítica de Células T/patología , Infiltración Leucémica/patología , Trombosis/patología , Anciano , Biopsia , Ecocardiografía , Electrocardiografía , Femenino , Atrios Cardíacos/patología , Neoplasias Cardíacas/diagnóstico por imagen , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico por imagen , Infiltración Leucémica/diagnóstico por imagen , Trombosis/diagnóstico por imagen

RESUMEN

Acute promyelocytic leukemia (APL) is associated with reciprocal and balanced chromosomal translocations always involving the Retinoic Acid Receptor alpha (RARalpha) gene on chromosome 17 and variable partner genes (X genes) on distinct chromosomes. RARalpha fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and STAT5b genes. As a consequence, X-RARalpha and RARalpha-X fusion genes are generated encoding aberrant fusion proteins that can interfere with X and/or RARalpha function. Here we will review the relevant conclusions and the open questions that stem from a decade of in vivo analysis of APL pathogenesis in the mouse in transgenic and knock-out models.

Asunto(s)

Leucemia Promielocítica Aguda/genética , Proteínas de Fusión Oncogénica/genética , Receptores de Ácido Retinoico/genética , Translocación Genética , Animales , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Receptor alfa de Ácido Retinoico

RESUMEN

MZF1 is a transcription factor belonging to the Krüppel family of zinc finger proteins, expressed in totipotent hemopoietic cells as well as in myeloid progenitors. Here we have inactivated Mzfi1 by gene targeting. Mzf1(-/-) mice develop lethal neoplasias characterized by the infiltration and complete disruption of the liver architecture by a monomorphic population of cells of myeloid origin reminiscent of human chloromas. Mzf1 inactivation results in a striking increase of the autonomous cell proliferation and of the ability of Mzf1(-/-) hemopoietic progenitors to sustain long-term hemopoiesis. These findings demonstrate that Mzf1 can act as a tumor/growth suppressor in the hemopoietic compartment.

Asunto(s)

División Celular/fisiología , Transformación Celular Neoplásica , Proteínas de Unión al ADN/fisiología , Genes Supresores de Tumor , Factores de Transcripción/fisiología , Dedos de Zinc , Animales , Células de la Médula Ósea/citología , Células Cultivadas , Proteínas de Unión al ADN/genética , Células Madre Hematopoyéticas/citología , Factores de Transcripción de Tipo Kruppel , Ratones , Ratones Noqueados , Factores de Tiempo , Factores de Transcripción/genética

RESUMEN

Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of differentiation and is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. As a consequence of the translocation, RARalpha variably fuses to the PML, PLZF, NPM, NuMA, and Stat5b genes (X genes), respectively, leading to the generation of RARalpha-X and X-RARalpha fusion genes. The aberrant chimeric proteins encoded by these genes, as well as the inactivation of the X and RARalpha functions, may exert a crucial role in leukemogenesis. To define the molecular genetics of APL and the contribution of each molecular event in APL pathogenesis, we have generated transgenic mice harboring X-RARalpha and/or RARalpha-X genes as well as mice where the various X genes have been inactivated by homologous recombination. Here we show that while the X-RARalpha fusion gene is crucial for leukemogenesis, the presence of RARalpha-X and the inactivation of X function are critical in modulating the onset as well as the phenotype of the leukemia.

Asunto(s)

Modelos Animales de Enfermedad , Leucemia Promielocítica Aguda/etiología , Ratones Transgénicos/genética , Animales , Humanos , Leucemia Promielocítica Aguda/genética , Ratones , Proteínas de Fusión Oncogénica/genética

RESUMEN

BACKGROUND: B7 family molecules are involved in T-B-cell communications after interaction with their ligands CD28 and CD152. They play a key role in costimulatory mechanisms and during antigen presentation by efficient antigen presenting cells. B7 molecules are usually absent or expressed at low intensity on B lymphocytes from healthy subjects. In this study, the authors addressed the questions of whether B7 molecules are expressed and modulated in vitro on malignant B lymphocytes from patients with chronic lymphoproliferative diseases of B-cell type and whether they are able to trigger allogenic T-cell reactions. METHODS: Malignant B cells from the peripheral blood of 32 patients with B-cell chronic lymphocytic leukemia, mantle cell lymphoma, hairy cell leukemia, and its variant form were investigated for the expression of B7 molecules on the cell surface and for the ability to trigger allogenic T lymphocytes in different experimental conditions. RESULTS: Flow cytometry analysis demonstrated that freshly isolated malignant B cells express B7 molecules and that their expression may be up-regulated by the in vitro triggering of the CD40 molecule. Furthermore, freshly isolated malignant B cells induce allogenic T-cell proliferation. The in vitro triggering of malignant B lymphocytes by CD40, alone and in combination with interleukin-4, elicits a strong allogenic T-cell proliferation. This T-cell proliferation is related mainly to the presence of B7 molecules on malignant and normal B lymphocytes. CONCLUSIONS: These findings indicate that malignant B cells are efficient antigen presenting cells. It might be suggested that vaccination with pulsed malignant B cells themselves or dendritic cells with in vitro preactivated tumor B cells may represent an alternative therapeutic approach in these patients to generate an antilymphoma T-cell response in vivo.

Asunto(s)

Antígenos CD/inmunología , Linfocitos B/inmunología , Antígeno B7-1/inmunología , Leucemia de Células Pilosas/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma de Células del Manto/inmunología , Glicoproteínas de Membrana/inmunología , Linfocitos T/inmunología , Adulto , Anticuerpos/inmunología , Anticuerpos/farmacología , Presentación de Antígeno/inmunología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos CD/biosíntesis , Linfocitos B/metabolismo , Antígeno B7-1/biosíntesis , Antígeno B7-2 , Antígenos CD40/inmunología , Femenino , Citometría de Flujo , Humanos , Leucemia de Células Pilosas/sangre , Leucemia Linfocítica Crónica de Células B/sangre , Activación de Linfocitos/inmunología , Linfoma de Células del Manto/sangre , Masculino , Glicoproteínas de Membrana/biosíntesis , Persona de Mediana Edad , Células Tumorales Cultivadas

RESUMEN

B- and T-cell recirculation is crucial for the function of the immune system, with the control of cell migration being mainly mediated by several chemokines and their receptors. In this study, we investigated the expression and function of CXCR3 on normal and malignant B cells from 65 patients with chronic lymphoproliferative disorders (CLDs). Although CXCR3 is lacking on CD5(+) and CD5(-) B cells from healthy subjects, it is expressed on leukemic B lymphocytes from all (31/31) patients with chronic lymphocytic leukemia (CLL). The presence of CXCR3 was heterogeneous in other B-cell disorders, being expressed in 2 of 7 patients with mantle cell lymphoma (MCL), 4 of 12 patients with hairy cell leukemia (HCL), and 11 of 15 patients with other subtypes of non-Hodgkin's lymphomas (NHLs). Chemotaxis assay shows that normal B cells from healthy subjects do not migrate in response to IFN-inducible protein 10 (IP-10) and IFN-gamma-induced monokine (Mig). In contrast, a definite migration in response to IP-10 and Mig has been observed in all malignant B cells from patients with CLL, but not in patients with HCL or MCL (1/7 cases tested). Neoplastic B cells from other NHLs showed a heterogenous pattern. The migration elicited by IP-10 and Mig was inhibited by blocking CXCR3. No effect of IP-10 and Mig chemokines was observed on the cytosolic calcium concentration in malignant B cells. The data reported here demonstrate that CXCR3 is expressed on malignant B cells from CLDs, particularly in patients with CLL, and represents a fully functional receptor involved in chemotaxis of malignant B lymphocytes.

Asunto(s)

Linfocitos B/fisiología , Quimiotaxis de Leucocito/fisiología , Leucemia de Células Pilosas/patología , Linfoma de Células B/patología , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas/fisiología , Receptores de Quimiocina/fisiología , Adulto , Anciano , Linfocitos B/química , Calcio/metabolismo , Quimiocina CXCL10 , Quimiocinas CXC/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Interferón gamma/farmacología , Leucemia de Células Pilosas/metabolismo , Linfoma de Células B/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/química , Receptores CXCR3 , Receptores de Quimiocina/biosíntesis , Receptores de Quimiocina/genética