Suppression of malignant rhabdoid tumors through Chb‐M′‐mediated RUNX1 inhibition

Abstract

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy primarily affecting infants and young children. Intensive multimodal therapies currently given to MRT patients are not sufficiently potent to control this highly malignant tumor. Therefore, additive or alternative therapy for these patients with a poor prognosis is necessary. We herein demonstrated that the inhibition of runt-related transcription factor 1 (RUNX1) by novel alkylating conjugated pyrrole-imidazole (PI) polyamides, which specifically recognize and bind to RUNX-binding DNA sequences, was highly effective in the treatment of rhabdoid tumor cell lines in vitro as well as in an in vivo mouse model. Therefore, suppression of RUNX1 activity may be a novel strategy for MRT therapy. K E Y W O R D S malignant rhabdoid tumor, p53, polyamide, RUNX1 1 BACKGROUND Malignant rhabdoid tumor (MRT) is a rare and highly aggressive malignancy, which affects infants and young children. 1 MRT occurs at various anatomical locations including the kidneys, central nervous system (CNS), liver, heart, mediastinum, uterus, adnexa, urinary blad-Abbreviations: Chb-M′, chlorambucil-M prime; MRT, malignant rhabdoid tumor der, and soft tissue. Despite the existing standard intensive multimodal therapy, the long-term survival rate of MRT patients is less than 30%. 2,3 Therefore, more effective treatments are highly desired. The genetic hallmark of rhabdoid tumors are mutations of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin-remodeling complex. SMARCB1 has potent tumor suppressor activity, and Wang et al reported that oncogenesis caused by loss of SMARCB1 might be dependent on the activity of the residual SWI/SNF

RUNX1–Survivin Axis Is a Novel Therapeutic Target for Malignant Rhabdoid Tumors

“…MP-MRT-AN, KP-MRT-RY, and KP-MRT-YM cells were established, as previously described ( Katsumi et al, 2011 ; Kuroda et al, 2005 ; Misawa et al, 2004 ). Cells were maintained in the Roswell Park Memorial Institute-1640 medium containing 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin–streptomycin, as previously reported ( Daifu et al, 2021 ). Cells were cultured at 37°C and 5% CO 2 .…”

“…Immunoblotting was performed as previously described ( Daifu et al, 2021 ; Morita et al, 2017a ). Cells were washed twice with ice-cold PBS and lysed in lysis buffer (50 mM Tris [pH 7.4], 100 mM NaCl, 0.1 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 1 mM Na3VO4, 1× protease inhibitor [Roche, Switzerland], and PhosSTOP [Roche]).…”