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Preclinical efficac...
Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy
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Cheung, LC (författare)
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Aya-Bonilla, C (författare)
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Cruickshank, MN (författare)
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visa fler...
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Chiu, SK (författare)
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Kuek, V (författare)
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Anderson, D (författare)
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Chua, GA (författare)
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Singh, S (författare)
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Oommen, J (författare)
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Ferrari, E (författare)
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Hughes, AM (författare)
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Ford, J (författare)
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Kunold, E (författare)
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Hesselman, MC (författare)
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Post, F (författare)
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Faulk, KE (författare)
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Breese, EH (författare)
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Guest, EM (författare)
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Brown, PA (författare)
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Loh, ML (författare)
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Lock, RB (författare)
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Kees, UR (författare)
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- Jafari, R (författare)
- Karolinska Institutet
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Malinge, S (författare)
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Kotecha, RS (författare)
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(creator_code:org_t)
- 2022-11-15
- 2023
- Engelska.
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 37:1, s. 61-71
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http://kipublication...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Publikations- och innehållstyp
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- art (ämneskategori)
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Leukemia
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Till lärosätets databas
- Av författaren/redakt...
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Cheung, LC
-
Aya-Bonilla, C
-
Cruickshank, MN
-
Chiu, SK
-
Kuek, V
-
Anderson, D
-
visa fler...
-
Chua, GA
-
Singh, S
-
Oommen, J
-
Ferrari, E
-
Hughes, AM
-
Ford, J
-
Kunold, E
-
Hesselman, MC
-
Post, F
-
Faulk, KE
-
Breese, EH
-
Guest, EM
-
Brown, PA
-
Loh, ML
-
Lock, RB
-
Kees, UR
-
Jafari, R
-
Malinge, S
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Kotecha, RS
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visa färre...
- Artiklar i publikationen
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Leukemia
- Av lärosätet
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Karolinska Institutet