Enhanced MAPK signaling induced by CSF3R mutants confers dependence to DUSP1 for leukemic transformation.
Blood Adv
; 8(11): 2765-2776, 2024 Jun 11.
Article
em En
| MEDLINE
| ID: mdl-38531054
ABSTRACT
ABSTRACT Elevated MAPK and the JAK-STAT signaling play pivotal roles in the pathogenesis of chronic neutrophilic leukemia and atypical chronic myeloid leukemia. Although inhibitors targeting these pathways effectively suppress the diseases, they fall short in providing enduring remission, largely attributed to the cytostatic nature of these drugs. Even combinations of these drugs are ineffective in achieving sustained remission. Enhanced MAPK signaling besides promoting proliferation and survival triggers a proapoptotic response. Consequently, malignancies reliant on elevated MAPK signaling use MAPK feedback regulators to intricately modulate the signaling output, prioritizing proliferation and survival while dampening the apoptotic stimuli. Herein, we demonstrate that enhanced MAPK signaling in granulocyte colony-stimulating factor 3 receptor (CSF3R)-driven leukemia upregulates the expression of dual specificity phosphatase 1 (DUSP1) to suppress the apoptotic stimuli crucial for leukemogenesis. Consequently, genetic deletion of Dusp1 in mice conferred synthetic lethality to CSF3R-induced leukemia. Mechanistically, DUSP1 depletion in leukemic context causes activation of JNK1/2 that results in induced expression of BIM and P53 while suppressing the expression of BCL2 that selectively triggers apoptotic response in leukemic cells. Pharmacological inhibition of DUSP1 by BCI (a DUSP1 inhibitor) alone lacked antileukemic activity due to ERK1/2 rebound caused by off-target inhibition of DUSP6. Consequently, a combination of BCI with a MEK inhibitor successfully cured CSF3R-induced leukemia in a preclinical mouse model. Our findings underscore the pivotal role of DUSP1 in leukemic transformation driven by enhanced MAPK signaling and advocate for the development of a selective DUSP1 inhibitor for curative treatment outcomes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Fator Estimulador de Colônias
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Sistema de Sinalização das MAP Quinases
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Fosfatase 1 de Especificidade Dupla
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Blood Adv
Ano de publicação:
2024
Tipo de documento:
Article