Low catalase expression confers redox hypersensitivity and identifies an indolent clinical behavior in CLL.
Blood
; 131(17): 1942-1954, 2018 04 26.
Article
en En
| MEDLINE
| ID: mdl-29467184
ABSTRACT
B-cell receptor (BCR) signaling is a key determinant of variable clinical behavior and a target for therapeutic interventions in chronic lymphocytic leukemia (CLL). Endogenously produced H2O2 is thought to fine-tune the BCR signaling by reversibly inhibiting phosphatases. However, little is known about how CLL cells sense and respond to such redox cues and what effect they have on CLL. We characterized the response of BCR signaling proteins to exogenous H2O2 in cells from patients with CLL, using phosphospecific flow cytometry. Exogenous H2O2 in the absence of BCR engagement induced a signaling response of BCR proteins that was higher in CLL with favorable prognostic parameters and an indolent clinical course. We identified low catalase expression as a possible mechanism accounting for redox signaling hypersensitivity. Decreased catalase could cause an escalated accumulation of exogenous H2O2 in leukemic cells with a consequent greater inhibition of phosphatases and an increase of redox signaling sensitivity. Moreover, lower levels of catalase were significantly associated with a slower progression of the disease. In leukemic cells characterized by redox hypersensitivity, we also documented an elevated accumulation of ROS and an increased mitochondrial amount. Taken together, our data identified redox sensitivity and metabolic profiles that are linked to differential clinical behavior in CLL. This study advances our understanding of the redox and signaling heterogeneity of CLL and provides the rationale for the development of therapies targeting redox pathways in CLL.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Leucemia Linfocítica Crónica de Células B
/
Transducción de Señal
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Catalasa
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Regulación Enzimológica de la Expresión Génica
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Regulación Leucémica de la Expresión Génica
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Proteínas de Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Blood
Año:
2018
Tipo del documento:
Article