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1.
Blood ; 135(15): 1244-1254, 2020 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-32006000

RESUMEN

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n = 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d+ subpopulation and a CD49d- subpopulation. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49d+ subpopulation over time after therapy. The CD49d+ subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d- cells; and was more highly represented in the bone marrow compared with peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49d+ subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d+ CLL, both in chemoimmunotherapy (n = 1522) and in ibrutinib (n = 158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should also be considered to improve the prognostic impact of this biomarker in CLL.


Asunto(s)
Integrina alfa4/análisis , Leucemia Linfocítica Crónica de Células B/patología , Adenina/análogos & derivados , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Humanos , Inmunoterapia , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/terapia , Piperidinas , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico
2.
Hematol Oncol ; 40(2): 181-190, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34783040

RESUMEN

CD49d, the α4 chain of the VLA-4 integrin, is a negative prognosticator in chronic lymphocytic leukemia (CLL) with a key role in CLL cell-microenvironment interactions mainly occurring via its ligands VCAM-1 and fibronectin. In the present study, we focused on EMILIN-1 (Elastin-MIcrofibriL-INterfacer-1), an alternative VLA-4 ligand whose role has been so far reported only in non-hematological settings, by investigating: i) the distribution of EMILIN-1 in CLL-involved tissues; ii) the capability of EMILIN-1 to operate, via its globular C1q (gC1q) domain, as additional adhesion ligand in CLL; iii) the functional meaning of EMILIN-1 gC1q/VLA-4 interactions in CLL. EMILIN-1 is widely present in the CLL-involved areas of bone marrow biopsies (BMBs) without difference between CD49d negative and positive cases, displaying at least three different expression patterns: "fibrillar", "dot-like" and "mixed". The lack in CLL-BMB of neutrophil elastase, whose proteolytic activity degrades EMILIN-1 and impairs EMILIN-1 function, suggests full functional EMILIN-1 in CLL independently of its expression pattern. Functionally, EMILIN-1 gC1q domain promotes adhesion of CLL cells through specific interaction with VLA-4, and releases pro-survival signals for CLL cells, as demonstrated by enhanced ERK and AKT phosphorylation and impairment of in-vitro-induced apoptosis. EMILIN-1/VLA-4 interaction can efficiently contribute to the maintenance of the neoplastic clone in CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Elastina , Humanos , Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Ligandos , Glicoproteínas de Membrana , Microfibrillas/metabolismo , Microfibrillas/patología , Microambiente Tumoral
3.
Blood ; 122(19): 3317-21, 2013 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-24068493

RESUMEN

CD49d is a negative prognosticator in chronic lymphocytic leukemia (CLL), expressed by ~40% of CLL cases and associated with aggressive, accelerated clinical courses. In this study, analyzing CD49d expression in a wide CLL cohort (n = 1200) belonging to different cytogenetic groups, we report that trisomy 12 CLL almost universally expressed CD49d and were characterized by the highest CD49d expression levels among all CD49d(+) CLL. Through bisulfite genomic sequencing, we demonstrated that, although CD49d(+)/trisomy 12 CLL almost completely lacked methylation of the CD49d gene, CD49d(-)/no trisomy 12 CLL were overall methylated, the methylation levels correlating inversely to CD49d expression (P = .0001). Consistently, CD49d expression was recovered in CD49d(-) hypermethylated CLL cells upon in vitro treatment with the hypomethylating agent 5-aza-2'-deoxycytidine. This may help explain the clinicobiological features of trisomy 12 CLL, including the high rates of cell proliferation and disease progression, lymph node involvement, and predisposition to Richter syndrome transformation.


Asunto(s)
Linfocitos B/metabolismo , Cromosomas Humanos Par 12 , Regulación Leucémica de la Expresión Génica , Integrina alfa4/genética , Leucemia Linfocítica Crónica de Células B/genética , Trisomía/patología , Azacitidina/análogos & derivados , Azacitidina/farmacología , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Proliferación Celular , Células Cultivadas , Decitabina , Progresión de la Enfermedad , Humanos , Integrina alfa4/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Metilación , Análisis de Secuencia de ADN , Transducción de Señal , Análisis de Supervivencia
5.
Dis Markers ; 2020: 8869424, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33343767

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread worldwide from the beginning of 2020. The presence of viral RNA in samples by nucleic acid (NA) molecular analysis is the only method available to diagnose COVID-19 disease and to assess patients' viral load. Since the demand for laboratory reagents has increased, there has been a worldwide shortage of RNA extraction kits. We, therefore, developed a fast and cost-effective viral genome isolation method that, combined with quantitative RT-PCR assay, detects SARS-CoV-2 RNA in patient samples. The method relies on the addition of Proteinase K followed by a controlled heat-shock incubation and, then, E gene evaluation by RT-qPCR. It was validated for sensitivity, specificity, linearity, reproducibility, and precision. It detects as low as 10 viral copies/sample, is rapid, and has been characterized in 60 COVID-19-infected patients. Compared to automated extraction methods, our pretreatment guarantees the same positivity rate with the advantage of shortening the time of the analysis and reducing its cost. This is a rapid workflow meant to aid the healthcare system in the rapid identification of infected patients, such as during a pathogen-related outbreak. For its intrinsic characteristics, this workflow is suitable for large-scale screenings.


Asunto(s)
Prueba de COVID-19/métodos , ARN Viral/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , SARS-CoV-2/genética , Proteínas de la Envoltura de Coronavirus/genética , Humanos , Límite de Detección , Nasofaringe/virología , Sensibilidad y Especificidad , Flujo de Trabajo
6.
Curr Cancer Drug Targets ; 16(8): 659-668, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27514846

RESUMEN

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the α chain of the α4ß1 integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. Treatment strategies targeting the α4ß1 integrin could represent an interesting option in CLL. In this context, the recombinant anti-CD49d antibody natalizumab demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the α4ß1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options.


Asunto(s)
Cadenas alfa de Integrinas/metabolismo , Integrina alfa4/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Humanos , Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico
7.
Semin Hematol ; 51(3): 168-76, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25048781

RESUMEN

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphologic appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. A combination of genetic lesions is primarily responsible for the first step(s) of neoplastic transformation, along with microenvironmental signals, which concurrently operate by enhancing proliferation and/or inhibiting apoptosis. In this context, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues, eventually delivering pro-survival signals and protecting CLL cells from drug-induced damages. In the present review, we address, in detail, CD49d activities in the CLL microenvironment, CD49d functional and physical interactions with other microenvironmental receptors (including CD38 and B-cell receptor), and the relationship of CD49d expression with specific cytogenetic features in CLL.


Asunto(s)
Integrina alfa4/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , Linfocitos B/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Transducción de Señal , Trisomía , Microambiente Tumoral
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