RESUMEN
Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Tumor Rabdoide , Survivin , Humanos , Apoptosis , Secuencia de Bases , Línea Celular Tumoral , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Tumor Rabdoide/tratamiento farmacológico , Tumor Rabdoide/genéticaRESUMEN
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.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Clorambucilo/uso terapéutico , Subunidad alfa 2 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Tumor Rabdoide/tratamiento farmacológico , Animales , Línea Celular Tumoral , Clorambucilo/análogos & derivados , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteína SMARCB1/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3-rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.
