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Sökning: WFRF:(Anderson KE) > Ferrari E.

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  • 2017
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  • Cheung, LC, et al. (författare)
  • Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy
  • 2023
  • Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 37:1, s. 61-71
  • Tidskriftsartikel (refereegranskat)abstract
    • Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL.
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  • Resultat 1-10 av 14
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Ferrari, E. (14)Ta bort avgränsningen
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