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

被引：27

作者：

Cheung, Laurence C. ^{[1
,2
,3
]}

Aya-Bonilla, Carlos ^{[1
,4
]}

Cruickshank, Mark N. ^{[4
]}

Chiu, Sung K. ^{[1
]}

Kuek, Vincent ^{[1
,2
,4
]}

Anderson, Denise ^{[1
]}

Chua, Grace-Alyssa ^{[1
]}

Singh, Sajla ^{[1
]}

Oommen, Joyce ^{[1
]}

Ferrari, Emanuela ^{[1
]}

Hughes, Anastasia M. ^{[1
]}

Ford, Jette ^{[1
]}

Kunold, Elena ^{[5
]}

Hesselman, Maria C. ^{[5
]}

Post, Frederik ^{[5
]}

Faulk, Kelly E. ^{[6
]}

Breese, Erin H. ^{[7
,8
]}

Guest, Erin M. ^{[9
]}

Brown, Patrick A. ^{[10
]}

Loh, Mignon L. ^{[11
]}

Lock, Richard B. ^{[12
]}

Kees, Ursula R. ^{[1
,4
]}

Jafari, Rozbeh ^{[5
]}

Malinge, Sebastien ^{[1
,4
]}

Kotecha, Rishi S. ^{[1
,2
,4
,13
]}

机构：

[1] Telethon Kids Inst, Telethon Kids Canc Ctr, Leukaemia Translat Res Lab, Perth, WA, Australia

[2] Curtin Univ, Curtin Med Sch, Perth, WA, Australia

[3] Curtin Univ, Curtin Hlth Innovat Res Inst, Perth, WA, Australia

[4] Univ Western Australia, Perth, WA, Australia

[5] Karolinska Inst, Dept Oncol Pathol Clin Prote Mass Spectrometry, Sci Life Lab, Solna, Sweden

[6] Univ Colorado, Childrens Hosp Colorado, Anschutz Med Campus, Aurora, CO USA

[7] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Div Oncol, Cincinnati, OH 45229 USA

[8] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA

[9] Childrens Mercy Kansas City, Div Hematol Oncol Blood & Marrow Transplantat, Kansas City, MO USA

[10] Johns Hopkins Univ, Div Pediat Oncol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA

[11] Seattle Childrens Hosp, Div Pediat Hematol Oncol Bone Marrow Transplant &, Seattle, WA USA

[12] UNSW Sydney, Childrens Canc Inst, UNSW Ctr Childhood Canc Res, Sch Womens & Childrens Hlth,Lowy Canc Res Ctr, Kensington, NSW, Australia

[13] Perth Childrens Hosp, Dept Clin Haematol Oncol Blood & Marrow Transplan, Perth, WA, Australia

来源：

LEUKEMIA | 2023年 / 37卷 / 01期

基金：

瑞典研究理事会; 英国医学研究理事会;

关键词：

IN-VIVO; TARGET; METHYLATION; BCL-2; GENE;

D O I：

10.1038/s41375-022-01746-3

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：61 / 71

页数：11

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