Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy.

Autor: Cheung LC; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.; Curtin Medical School, Curtin University, Perth, WA, Australia.; Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia., Aya-Bonilla C; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.; The University of Western Australia, Perth, WA, Australia., Cruickshank MN; The University of Western Australia, Perth, WA, Australia., Chiu SK; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Kuek V; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.; Curtin Medical School, Curtin University, Perth, WA, Australia.; The University of Western Australia, Perth, WA, Australia., Anderson D; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Chua GA; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Singh S; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Oommen J; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Ferrari E; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Hughes AM; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Ford J; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia., Kunold E; Department of Oncology-Pathology, Clinical Proteomics Mass Spectrometry, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden., Hesselman MC; Department of Oncology-Pathology, Clinical Proteomics Mass Spectrometry, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden., Post F; Department of Oncology-Pathology, Clinical Proteomics Mass Spectrometry, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden., Faulk KE; University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO, USA., Breese EH; Cancer and Blood Diseases Institute, Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Guest EM; Division of Hematology, Oncology, Blood and Marrow Transplantation, Children's Mercy Kansas City, Kansas City, MO, USA., Brown PA; Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, MD, USA., Loh ML; Division of Pediatric Hematology, Oncology, Bone Marrow Transplant and Cellular Therapy, Seattle Children's Hospital, Seattle, WA, USA., Lock RB; Children's Cancer Institute, Lowy Cancer Research Centre/School of Women's and Children's Health/UNSW Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia., Kees UR; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.; The University of Western Australia, Perth, WA, Australia., Jafari R; Department of Oncology-Pathology, Clinical Proteomics Mass Spectrometry, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden., Malinge S; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.; The University of Western Australia, Perth, WA, Australia., Kotecha RS; Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia. rishi.kotecha@health.wa.gov.au.; Curtin Medical School, Curtin University, Perth, WA, Australia. rishi.kotecha@health.wa.gov.au.; The University of Western Australia, Perth, WA, Australia. rishi.kotecha@health.wa.gov.au.; Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children's Hospital, Perth, WA, Australia. rishi.kotecha@health.wa.gov.au.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2023 Jan; Vol. 37 (1), pp. 61-71. Date of Electronic Publication: 2022 Nov 15.
DOI: 10.1038/s41375-022-01746-3
Abstrakt: 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.
(© 2022. Crown.)
Databáze: MEDLINE
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