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

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.

A RUNX-targeted gene switch-off approach modulates the BIRC5/PIF1-p21 pathway and reduces glioblastoma growth in mice.

Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma.

Suppression of malignant rhabdoid tumors through Chb-M'-mediated RUNX1 inhibition.

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.

Influence of post-transplant mucosal-associated invariant T cell recovery on the development of acute graft-versus-host disease in allogeneic bone marrow transplantation.

Mucosal-associated invariant T (MAIT) and invariant natural killer T (iNKT) cells are T cell subpopulations that possess innate-like properties. We examined the impact of post-hematopoietic stem cell transplantation (HSCT) MAIT and iNKT cell recovery on the clinical outcomes of 69 patients who underwent allogeneic HSCT at Kyoto University Hospital. Multivariate analyses identified the absolute number of MAIT cells (< 0.48/µL on day 60 post-HSCT) as the sole independent risk factor for grade I-IV and grade II-IV acute graft-versus-host disease (aGVHD) among patients who underwent bone marrow transplantation; no correlation was observed between post-HSCT iNKT cell recovery and the development of aGVHD. Six of the 15 patients in the MAIThigh (≥ 0.48/µL) group developed aGVHD, five within the first 30 days post HSCT. In contrast, 13 of the 15 patients in the MAITlow (< 0.48/µL) group developed aGVHD, seven after day 30 post HSCT. The overall survival of the MAITlow group was slightly shorter than that of the MAIThigh group. Thus, the post-HSCT recovery of MAIT cells is closely related to the development of delayed onset aGVHD and the outcome of post-HSCT, suggesting its utility for identifying a subset of patients that requires more prolonged and/or intense GVHD prophylaxis.

Impact of post-transplant minimal residual disease on the clinical outcome of pediatric acute leukemia.

This retrospective study examined the clinical significance of FCM-MRD in 36 patients with ALL and 29 patients with AML after their first allogeneic HSCT. Hematological (FCM-MRD ≥5.0%) and molecular relapse (FCM-MRD <5.0%) were first detected in 10 and two patients with ALL and in seven and eight patients with AML, respectively. Eight of 10 patients with molecular relapse eventually progressed to hematological relapse, although most were treated with immunological intervention by aggressive discontinuation of immunosuppressive therapy or donor lymphocyte infusion. Among these 12 patients, four of seven patients that obtained MRDneg CR following post-transplant chemotherapy remain alive and disease-free after their second HSCT; however, all five patients who underwent a second HSCT in non-CR died of disease or treatment-related complications. As the FCM-MRD monitoring system used in the current study was probably not sensitive enough to detect MRD, which could be elucidated by immunological intervention, more sensitive diagnostic tools are mandatory for post-transplant MRD monitoring. Additional studies are required to address the impact of presecond transplant MRD on the clinical outcome of second HSCT.

Vaccine-strain herpes zoster found in the trigeminal nerve area in a healthy child: A case report.

A previously healthy 2-year-old girl, vaccinated for varicella at 17 months, was admitted because of left-sided facial herpes zoster caused by vaccine-strain varicella-zoster virus (VZV). She recovered fully with no complication after intravenous treatment using acyclovir. Earlier reports have described that herpes zoster (HZ) rashes caused by vaccine-strain VZV tend to occur on the dermis corresponding to the skin area where the varicella vaccine was received. However, rashes appeared on this girl only in the trigeminal nerve area, which is unrelated to the vaccinated site. Results underscore the importance of distinguishing vaccine-strain VZV from wild-type VZV whenever encountering HZ cases after vaccination, even in immunocompetent children, irrespective of the skin lesion site. Monitoring vaccine-strain HZ incidence rates is expected to elucidate many aspects of varicella vaccine safety.

Impact of pretransplant minimal residual disease on the post-transplant outcome of pediatric acute lymphoblastic leukemia.

There are few reports on the clinical significance of MRD before HSCT in pediatric ALL. We retrospectively analyzed the clinical significance of FCM-based detection of MRD (FCM-MRD) before allogeneic HSCT in pediatric ALL. Of 38 pediatric patients who underwent allogeneic HSCT for the first time between 1998 and 2014, 33 patients were in CR and five patients were in non-CR. The CR group was further divided into two groups based on the pretransplant FCM-MRD level: the MRD(neg) (<0.01%; 30 patients) group and the MRD(pos) (≥0.01%; three patients) group. There were significant differences in the three-yr event-free survival rates between the CR and non-CR group, and between the MRD(neg) and MRD(pos) group. The three-yr cumulative RI in the MRD(neg) group were 27.3% ± 8.8%, whereas two of the three patients in the MRD(pos) group relapsed within one yr after HSCT. The clinical outcome of the MRD(pos) group was as poor as that of the non-CR group in pediatric ALL. Therefore, an improvement in pretransplant treatment that aims to achieve a more profound remission would contribute to reducing the risk of relapse.

Somatic mosaicism for a NRAS mutation associates with disparate clinical features in RAS-associated leukoproliferative disease: a report of two cases.

RAS-associated leukoproliferative disease (RALD) is a newly classified disease; thus its clinical features and management are not fully understood. The cases of two patients with characteristic features of RALD are described herein. Patient 1 was a 5-month-old female with clinical features typical of autoimmune lymphoproliferative syndrome (ALPS) and markedly elevated TCRαß(+)CD4(-)CD8(-) T cell numbers. Genetic analyses failed to detect an ALPS-related gene mutation; however, whole exome sequencing and other genetic analyses revealed somatic mosaicism for the G13D NRAS mutation. These data were indivative of NRAS-associated RALD with highly elevated αß-double-negative T cells. Patient 2 was a 12-month-old girl with recurrent fever who clearly met the diagnostic criteria for juvenile myelomonocytic leukemia (JMML). Genetic analyses revealed somatic mosaicism, again for the G13D NRAS mutation, suggesting RALD associated with somatic NRAS mosaicism. Notably, unlike most JMML cases, Patient 2 did not require steroids or hematopoietic stem cell transplantation. Genetic analysis of RAS should be performed in patients fulfilling the diagnostic criteria for ALPS in the absence of ALPS-related gene mutations if the patients have elevated αß-double-negative-T cells and in JMML patients if autoimmunity is detected. These clinical and experimental data increase our understanding of RALD, ALPS, and JMML.

Refeeding syndrome in a small-for-dates micro-preemie receiving early parenteral nutrition.

This report describes a small-for-date extremely low birth weight infant who manifested bradycardic events, respiratory failure, and hemolytic jaundice during her first week of life. These complications were attributed to severe hypophosphatemia and hypokalemia. Inadequate supply and refeeding syndrome triggered by early aggressive parenteral nutrition were responsible for electrolyte abnormalities.