High-Throughput Drug Library Screening in Primary KMT2A-Rearranged Infant ALL Cells Favors the Identification of Drug Candidates That Activate P53 Signaling

被引：4

作者：

Wander, Priscilla ^{[1
,2
]}

Arentsen-Peters, Susan T. C. J. M. ^{[1
]}

Vrenken, Kirsten S. ^{[1
]}

Pinhancos, Sandra Mimoso ^{[1
,3
]}

Koopmans, Bianca ^{[1
]}

Dolman, M. Emmy M. ^{[1
,4
,5
]}

Jones, Luke ^{[1
]}

Castro, Patricia Garrido ^{[1
]}

Schneider, Pauline ^{[1
]}

Kerstjens, Mark ^{[2
]}

Molenaar, Jan J. ^{[1
,6
]}

Pieters, Rob ^{[1
]}

Zwaan, Christian Michel ^{[1
,2
]}

Stam, Ronald W. ^{[1
]}

机构：

[1] Princess Maxima Ctr Pediat Oncol, NL-3584 CS Utrecht, Netherlands

[2] Erasmus MC, Dept Pediat Oncol Hematol, Sophia Childrens Hosp, NL-3015 CN Rotterdam, Netherlands

[3] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004504 Coimbra, Portugal

[4] UNSW Sydney, Childrens Canc Inst, Lowy Canc Ctr, Sydney, NSW 2052, Australia

[5] Univ New South Wales, Fac Med, Sch Womens & Childrens Hlth, Sydney, NSW 2031, Australia

[6] Univ Utrecht, Dept Pharmaceut Sci, NL-3584 CS Utrecht, Netherlands

来源：

BIOMEDICINES | 2022年 / 10卷 / 03期

基金：

美国国家卫生研究院;

关键词：

MLL-rearrangements; acute lymphoblastic leukemia; infant ALL; p53; drug library screening; ACUTE LYMPHOBLASTIC-LEUKEMIA; MLL TRANSLOCATIONS; H3K79; METHYLATION; BREAST-CANCER; INHIBITORS; IRINOTECAN; MODELS; ISOLIQUIRITIGENIN; ANTAGONIST; MECHANISMS;

D O I：

10.3390/biomedicines10030638

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slowpaced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing.

引用

页数：15