The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-kappa B signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-kappa B, biochemical studies revealed the presence of constitutive noncanonical NF-kappa B activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53 abnormalities. (Blood. 2012; 119(12): 2854-2862)

Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia / D., Rossi; M., Fangazio; S., Rasi; T., Vaisitti; S., Monti; S., Cresta; Chiaretti, Sabina; DEL GIUDICE, Ilaria; G., Fabbri; A., Bruscaggin; V., Spina; C., Deambrogi; Marinelli, Marilisa; R., Fama; M., Greco; G., Daniele; F., Forconi; V., Gattei; F., Bertoni; S., Deaglio; L., Pasqualucci; Guarini, Anna; R., Dalla Favera; Foa, Roberto; G., Gaidano. - In: BLOOD. - ISSN 0006-4971. - 119:12(2012), pp. 2854-2862. [10.1182/blood-2011-12-395673]

Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia

CHIARETTI, sabina;DEL GIUDICE, ILARIA;MARINELLI, MARILISA;GUARINI, Anna;FOA, Roberto;
2012

Abstract

The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-kappa B signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-kappa B, biochemical studies revealed the presence of constitutive noncanonical NF-kappa B activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53 abnormalities. (Blood. 2012; 119(12): 2854-2862)
2012
01 Pubblicazione su rivista::01a Articolo in rivista
Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia / D., Rossi; M., Fangazio; S., Rasi; T., Vaisitti; S., Monti; S., Cresta; Chiaretti, Sabina; DEL GIUDICE, Ilaria; G., Fabbri; A., Bruscaggin; V., Spina; C., Deambrogi; Marinelli, Marilisa; R., Fama; M., Greco; G., Daniele; F., Forconi; V., Gattei; F., Bertoni; S., Deaglio; L., Pasqualucci; Guarini, Anna; R., Dalla Favera; Foa, Roberto; G., Gaidano. - In: BLOOD. - ISSN 0006-4971. - 119:12(2012), pp. 2854-2862. [10.1182/blood-2011-12-395673]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/474041
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