Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia.
Adv Sci (Weinh)
; 11(11): e2305885, 2024 Mar.
Article
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| MEDLINE
| ID: mdl-38161214
ABSTRACT
Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV-sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV-susceptible and DA-resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA-resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL-1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.
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Bases de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
Límite:
Adult
/
Humans
Idioma:
En
Revista:
Adv Sci (Weinh)
Año:
2024
Tipo del documento:
Article