High-Throughput Drug Library Screening in Primary <i>KMT2A</i>-Rearranged Infant ALL Cells Favors the Identification of Drug Candidates That Activate P53 Signaling
Priscilla Wander,
Susan T. C. J. M. Arentsen-Peters,
Kirsten S. Vrenken,
Sandra Mimoso Pinhanҫos,
Bianca Koopmans,
M. Emmy M. Dolman,
Luke Jones,
Patricia Garrido Castro,
Pauline Schneider,
Mark Kerstjens,
Jan J. Molenaar,
Rob Pieters,
Christian Michel Zwaan,
Ronald W. Stam
Affiliations
Priscilla Wander
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Susan T. C. J. M. Arentsen-Peters
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Kirsten S. Vrenken
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Sandra Mimoso Pinhanҫos
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Bianca Koopmans
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
M. Emmy M. Dolman
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Luke Jones
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Patricia Garrido Castro
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Pauline Schneider
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Mark Kerstjens
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands
Jan J. Molenaar
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Rob Pieters
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Christian Michel Zwaan
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Ronald W. Stam
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (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.
