학술논문
Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy
Document Type
Original Paper
Author
Cheung, Laurence C.; Aya-Bonilla, Carlos; Cruickshank, Mark N.; Chiu, Sung K.; Kuek, Vincent; Anderson, Denise; Chua, Grace-Alyssa; Singh, Sajla; Oommen, Joyce; Ferrari, Emanuela; Hughes, Anastasia M.; Ford, Jette; Kunold, Elena; Hesselman, Maria C.; Post, Frederik; Faulk, Kelly E.; Breese, Erin H.; Guest, Erin M.; Brown, Patrick A.; Loh, Mignon L.; Lock, Richard B.; Kees, Ursula R.; Jafari, Rozbeh; Malinge, Sébastien; Kotecha, Rishi S.
Source
Leukemia. 37(1):61-71
Subject
Language
English
ISSN
0887-6924
1476-5551
1476-5551
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.