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1.
Br J Haematol ; 193(3): 556-560, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33851417

RESUMEN

The clinical significance of low-frequency deletions of 17p13 [tumour protein p53 (TP53)] in patients with chronic lymphocytic leukaemia (CLL) is currently unclear. Low-frequency del17p clones (<25%) were identified in 15/95 patients in the Australasian Leukaemia and Lymphoma Group (ALLG)/CLL Australian Research Consortium (CLLARC) CLL5 trial. Patients with low del17p, without tumour protein p53 (TP53) mutation, had significantly longer progression-free survival and overall survival durations than patients with high del17p clones. In 11/15 cases with low-frequency del17p, subclones solely with del17p or del13q were also noted. These data suggest that low-frequency del17p does not necessarily confer a poor outcome in CLL and challenges the notion of del13q as a founding event in CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/mortalidad , Adulto , Australia/epidemiología , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Supervivencia sin Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genética
2.
Br J Haematol ; 186(5): 668-684, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31364161

RESUMEN

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk.


Asunto(s)
Citogenética/métodos , Leucemia Linfocítica Crónica de Células B/patología , Humanos , Leucemia Linfocítica Crónica de Células B/genética
3.
Br J Haematol ; 182(5): 654-669, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29978459

RESUMEN

Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan-PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL-202 in CLL. Importantly, IBL-202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL-202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL-202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug-resistance.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Integrina alfa4/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores CXCR4/metabolismo , Células Tumorales Cultivadas , Microambiente Tumoral
4.
Br J Haematol ; 182(3): 360-372, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29767411

RESUMEN

The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA). Binimetinib was also significantly more toxic towards CLL cells cultured in the presence of either anti-IgM antibody or stroma-derived factor-1α (SDF-1α) and reduced CLL cell cycle progression and proliferation. Furthermore, binimetinib significantly increased the sensitivity of CLL cells co-cultured with CD40 ligand (CD40L)-expressing fibroblasts to the BH3-mimetics ABT-737 and Venetoclax (ABT-199) via a mechanism involving down-regulation of Mcl-1 (MCL1) activity and Bim (BCL2L11) and Bcl-xL (BCL2L1) expression. Collectively, these data suggest that binimetinib may have both cytotoxic and cytostatic effects on CLL cells by blocking microenvironment-derived signals known to drive survival and proliferation. The combination of binimetinib with a BH3 mimetic may be an effective treatment strategy for CLL, particularly against the proliferative fraction of the disease within the tumour microenvironment.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Leucemia Linfocítica Crónica de Células B/patología , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos de Bifenilo/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Evaluación Preclínica de Medicamentos/métodos , Sinergismo Farmacológico , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nitrofenoles/farmacología , Piperazinas/farmacología , Sulfonamidas/farmacología , Células Tumorales Cultivadas
5.
Br J Haematol ; 181(1): 97-101, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29468645

RESUMEN

Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment-free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL.


Asunto(s)
Deficiencia de IgG , Inmunidad Humoral , Leucemia Linfocítica Crónica de Células B , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Deficiencia de IgG/sangre , Deficiencia de IgG/inmunología , Deficiencia de IgG/mortalidad , Deficiencia de IgG/terapia , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Tasa de Supervivencia
6.
Br J Haematol ; 168(3): 350-60, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25256787

RESUMEN

Chronic lymphocytic leukaemia (CLL) occurs rarely with pregnancy and monoclonal B-Lymphocytosis (MBL) has not previously been described in this setting. CLL is predominantly a disease of the elderly and affects men twice as often as women and hence only an estimated 2% of patients are females of childbearing age. We identified only five reported cases of CLL in pregnancy in the literature. We describe two additional cases, plus three other women with CLL dealing with pregnancy-related decisions. We review the literature and discuss proposals for management and issues that arise in this relatively uncommon occurrence. In contrast to many other haematological malignancies where longer remissions are typically associated with a lower risk of relapse, most patients with CLL who require treatment will ultimately relapse with current therapy. This complex setting requires careful consideration and well informed patients to assist with decisions related to pregnancy.


Asunto(s)
Linfocitos B/patología , Leucemia Linfocítica Crónica de Células B/terapia , Linfocitosis/terapia , Complicaciones Neoplásicas del Embarazo/terapia , Adulto , Toma de Decisiones , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Linfocitosis/diagnóstico , Atención Preconceptiva/métodos , Embarazo , Complicaciones Neoplásicas del Embarazo/diagnóstico , Adulto Joven
7.
Leuk Lymphoma ; 65(2): 242-249, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37933638

RESUMEN

In humans, AMPylation of cellular proteins is carried out by Huntingtin yeast-interacting protein E (HYPE), activated under conditions of endoplasmic reticulum stress, such as in cancer cells. Extracts of the human chronic lymphocytic leukemia cell line, OSU-CLL, were fractionated using immuno-precipitation with antibodies against adenosine-phosphate and then AMP-Tyr. The proteins isolated were modified with AMP, the 'AMPylome.' AMP-labelled peptides isolated from HYPE wild-type (WT) and HYPE knock-out (KO) cells were identified using tandem mass spectrometry. A total of 213 proteins were identified from WT cell extracts, while only 23 of these were pulled down from KO cells, consistent with the presence of another AMPylator, besides HYPE. The KO cells were more sensitive to fludarabine nucleoside (2-FaraA) than WT cells. Ingenuity Pathway Analysis of the AMPylated proteins identified in WT cells clustered actin binding proteins of the cytoskeleton, and proteins of the RHO GTPase pathway that would jointly stimulate cell proliferation.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Línea Celular , Estrés del Retículo Endoplásmico , Adenosina Monofosfato/metabolismo , Vidarabina
8.
Leuk Lymphoma ; 65(5): 585-597, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38227293

RESUMEN

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family. The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.


Asunto(s)
Apoptosis , Compuestos Bicíclicos Heterocíclicos con Puentes , Sinergismo Farmacológico , Leucemia Linfocítica Crónica de Células B , Sulfonamidas , Humanos , Sulfonamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Respuesta de Proteína Desplegada/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Transducción de Señal/efectos de los fármacos
9.
J Proteome Res ; 12(4): 1710-22, 2013 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-23458665

RESUMEN

The proteomic effects of the Hsp90 inhibitor, SNX-7081, have been determined on the p53-mutated B-cell chronic lymphocytic leukemia (CLL) cell line, MEC1. Following SNX-7081 treatment (500 nM, 24 h), 51 proteins changed abundance by more than 2-fold (p < 0.05); 7 proteins increased while 44 proteins decreased. Proteins identified as differentially abundant by LC-MS/MS were validated by Western blotting (DDB1, PCNA, MCM2, Hsp90, Hsp70, GRP78, PDIA6, HLA-DR). RT-PCR showed that SNX-7081 unexpectedly modulates a number of these proteins in MEC1 cells at the mRNA level (PCNA, MCM2, Nup155, Hsp70, GRP78, PDIA6, and HLA-DR). Pathway analysis determined that 3 of the differentially abundant proteins (cyclin D1, c-Myc and pRb) were functionally related. p53 levels did not change upon SNX-7081 treatment of p53 wild-type Raji cells or p53-mutated MEC1 and U266 cells, indicating that SNX-7081 has a p53-independent mechanism. The decreases in DDB1, MCM2, c-Myc, and PCNA and increases of pRb and cyclin D1 were confirmed in MEC1, U266, Raji, and p53 null HL60 cells by Western blotting. These data suggest that SNX-7081 arrests the cell cycle and inhibits DNA replication and r epair and provides evidence for the mechanism of the observed synergy between Hsp90 inhibitors and drugs that induce DNA strand breaks.


Asunto(s)
Benzamidas/farmacología , Ciclo Celular/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteoma/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Replicación del ADN/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Genes p53 , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Proteoma/análisis , Proteoma/genética , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem
11.
J Pharm Pharm Sci ; 16(2): 231-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23958192

RESUMEN

PURPOSE: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, some patients may survive for many years, while 20-30% of patients progress and may die within several years. Currently, there is not a single procedure that enables accurate prognosis and triaging of those patients who need immediate and aggressive treatment. All CLL cells are characterised by the expression of the B-cell antigens CD19, CD20, CD21, CD22 and CD23, with aberrant expression of the T-cell antigen CD5. METHODS: We have developed a CD antibody microarray (DotScan) containing 182 immobilised CD antibodies that has been used to obtain extensive surface profiles of CLL cells obtained from 96 patients. RESULTS: Of these 182 antigens, 27 were significantly differentially expressed between stable, stable-progressive and progressive CLL. Some of these antigens are not expressed on normal B-cells and may be targets for therapeutic antibodies against CLL. Unsupervised hierarchical clustering of the surface profiles from 96 patients showed that those with progressive CLL could be distinguished based solely upon this 'disease signature'. The sensitivity (proportion of actual positives correctly identified) was 67.9%, the specificity (proportion of negatives correctly identified) was 77.5%, and the accuracy was 71.9%. CONCLUSIONS: Considerable effort by a number of research groups has resulted in identification of individual markers for progressive CLL, but their collective use is yet to provide a test that identifies CLL patients at risk. Data presented here provide a basis for development of a simple test using an antibody microarray.


Asunto(s)
Antígenos CD/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Anticuerpos/inmunología , Progresión de la Enfermedad , Humanos , Análisis por Micromatrices
12.
Artículo en Inglés | MEDLINE | ID: mdl-34886743

RESUMEN

Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Línea Celular , Ciclofosfamida , Humanos , Neoplasias/tratamiento farmacológico , Nucleósidos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Vidarabina/análogos & derivados , Vidarabina/farmacología
13.
Br J Haematol ; 151(2): 185-8, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20738310

RESUMEN

Inhibitors of heat-shockprotein 90 (Hsp90) have been proposed as a novel therapeutic option for Chronic Lymphocytic Leukaemia (CLL), particularly as their mechanism of action appears independent of mutations of ATM or TP53. We investigated the activity of a novel Hsp90 inhibitor, SNX7081, against a panel of eight haematological cell lines and 23 CLL patient samples. SNX7081 displayed significant effects on cell cycle distribution, apoptotic rate and levels of ZAP-70 in the cell lines and in the patient samples, irrespective of TP53 status. Our findings suggest SNX7081 may represent a promising therapeutic option for aggressive CLL.


Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Benzoquinonas/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/farmacología , Leucemia Linfocítica Crónica de Células B/patología , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Genes p53/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Mutación , Proteínas de Neoplasias/metabolismo , Células Tumorales Cultivadas , Proteína Tirosina Quinasa ZAP-70/metabolismo
14.
Blood Adv ; 4(20): 5093-5106, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-33085757

RESUMEN

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α-induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Sulfonamidas/farmacología , Microambiente Tumoral
15.
Cell Physiol Biochem ; 24(5-6): 347-60, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19910675

RESUMEN

BACKGROUND: Deletion of phenylalanine-508 (DeltaF508) from the first nucleotide-binding domain (NBD1) in the wild-type cystic fibrosis (CF) transmembrane-conductance regulator (wtCFTR) causes CF. However, the mechanistic relationship between DeltaF508-CFTR and the diversity of CF disease is unexplained. The surface location of F508 on NBD1 creates the potential for protein-protein interactions and nearby, lies a consensus sequence (SYDE) reported to control the pleiotropic protein kinase CK2. METHODS: Electrophysiology, immunofluorescence and biochemistry applied to CFTR-expressing cells, Xenopus oocytes, pancreatic ducts and patient biopsies. RESULTS: Irrespective of PKA activation, CK2 inhibition (ducts, oocytes, cells) attenuates CFTR-dependent Cl(-) transport, closing wtCFTR in cell-attached membrane patches. CK2 and wtCFTR co-precipitate and CK2 co-localized with wtCFTR (but not DeltaF508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and DeltaF508CFTR expressing oocytes, only DeltaF508-CFTR Cl(-) currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the DeltaF508-equivalent peptide had no effect. CONCLUSIONS: CK2 controls wtCFTR, but not DeltaF508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by DeltaF508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR.


Asunto(s)
Quinasa de la Caseína II/metabolismo , Canales de Cloruro/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Regulación Alostérica , Secuencia de Aminoácidos , Animales , Transporte Biológico , Quinasa de la Caseína II/análisis , Quinasa de la Caseína II/antagonistas & inhibidores , Línea Celular , Cricetinae , AMP Cíclico/metabolismo , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/análisis , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fenómenos Electrofisiológicos , Cobayas , Humanos , Inmunoprecipitación , Datos de Secuencia Molecular , Mutación , Oocitos/metabolismo , Dominios y Motivos de Interacción de Proteínas , Xenopus
16.
Leuk Lymphoma ; 60(7): 1632-1643, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30648436

RESUMEN

Several key pathways mediate signaling via the B-cell receptor, including the mitogen-activated protein kinase-ERK1/2 pathway. However, inhibition of MEK1/2, a key component of the MAPK-ERK1/2 signaling cascade, results in paradoxical activation of AKT in chronic lymphocytic leukemia (CLL) cells. In the current study we demonstrate synergy between the MEK1/2 inhibitor binimetinib and the AKT inhibitor MK2206, which combined induce apoptosis of primary CLL cells and restrict the cell cycle progression and proliferation of the OSU-CLL cell line. The mechanisms of action of the drug combination involve dual inhibition of MAPK-ERK1/2 and AKT signaling and down-regulation of Mcl-1 expression. Collectively, these data suggest that dual inhibition of MEK1/2 and AKT may represent a therapeutic option for CLL, capable of overcoming the pro-survival effects of the lymph node and bone marrow microenvironments.


Asunto(s)
Apoptosis/efectos de los fármacos , Bencimidazoles/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Leucemia Linfocítica Crónica de Células B/patología , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Técnicas de Cocultivo , Quimioterapia Combinada , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos
17.
Leuk Lymphoma ; 59(8): 1927-1937, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29164976

RESUMEN

The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScan™ antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion. The immunophenotypic changes identified may provide further insight into the mechanisms by which CLL cells interact with the tumor microenvironment and better define how ibrutinib and idelalisib release CLL cells from the lymph nodes and bone marrow.


Asunto(s)
Adhesión Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Purinas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Quinazolinonas/farmacología , Microambiente Tumoral/efectos de los fármacos , Adenina/análogos & derivados , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Adhesión Celular/inmunología , Técnicas de Cocultivo , Fibroblastos/efectos de los fármacos , Fibroblastos/inmunología , Fibroblastos/metabolismo , Humanos , Inmunofenotipificación , Células L , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Activación de Linfocitos/inmunología , Ratones , Piperidinas , Células Tumorales Cultivadas , Microambiente Tumoral/inmunología
19.
Cell Signal ; 18(10): 1595-603, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16466905

RESUMEN

Cystic fibrosis (CF) results from mutations within the cystic fibrosis transmembrane-conductance regulator (CFTR) protein. The AMP-activated protein kinase (AMPK) is a heterotrimer composed of different isoforms of the alphabetagamma subunits, where the alpha1 catalytic subunit binds CFTR. Nucleoside diphosphate kinase (NDPK, NM23/awd) converts nucleoside diphosphates to nucleoside triphosphates but also acts as a protein kinase. We recently showed that AMPK alpha1 binds NDPK-A in lung epithelial cytosol. Here we report that in the plasma membrane of human airway epithelial cells, NDPK-A and AMPK alpha1 associate with the plasma membrane via CFTR. We show that the regulatory domain of CFTR binds NDPK-A whereas AMPK gamma1 or gamma2 bind the first nucleotide binding domain (NBD1) and AMPK alpha1 binds the second (NBD2) of CFTR. We also show that NDPK-A specifically binds AMPK alpha1 and AMPK gamma2 subunits, thereby specifying the isozyme of AMPK heterotrimer that associates with CFTR at the membrane. Thus, the combined data provide novel insight into the subunit composition of the epithelial CFTR/AMPK/NDPK complex, such that: CFTR interacts specifically with AMPK alpha1, gamma2 and NDPK-A and not NDPK-B or AMPK gamma1.


Asunto(s)
Membrana Celular/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Células Epiteliales/metabolismo , Complejos Multienzimáticos/metabolismo , Nucleósido-Difosfato Quinasa/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Animales , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Humanos , Pulmón/citología , Ratones , Modelos Biológicos , Nucleósido-Difosfato Quinasa/deficiencia , Nucleótidos/metabolismo , Unión Proteica
20.
Methods Mol Biol ; 1619: 263-301, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28674892

RESUMEN

DotScan antibody microarrays were initially developed for the extensive surface profiling of live leukemia and lymphoma cells. DotScan's diagnostic capability was validated with an extensive clinical trial using mononuclear cells from the blood or bone marrow of leukemia or lymphoma patients. DotScan has also been used for the profiling of surface proteins on peripheral blood mononuclear cells (PBMC) from patients with HIV, liver disease, and stable and progressive B-cell chronic lymphocytic leukemia (CLL). Fluorescence multiplexing allowed the simultaneous profiling of cancer cells and leukocytes from disaggregated colorectal and melanoma tumor biopsies after capture on DotScan. In this chapter, we have used DotScan for the surface profiling of extracellular vesicles (EV) recovered from conditioned growth medium of cancer cell lines and the blood of patients with CLL. The detection of captured EV was performed by enhanced chemiluminescence (ECL) using biotinylated antibodies that recognized antigens expressed on the surface of the EV subset of interest. DotScan was also used to profile EV from the blood of healthy individuals and the ascites fluid of ovarian cancer patients. DotScan binding patterns of EV from human plasma and other body fluids may yield diagnostic or prognostic signatures for monitoring the incidence, treatment, and progression of cancers.


Asunto(s)
Anticuerpos , Ascitis , Vesículas Extracelulares , Plasma , Análisis por Matrices de Proteínas/métodos , Anticuerpos/inmunología , Antígenos CD , Biomarcadores , Línea Celular , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucocitos Mononucleares , Mediciones Luminiscentes/métodos , Neoplasias Ováricas/sangre , Plasma/química
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