A5101674219- Acute Myeloid Leukemia Research
- Cancer-related Molecular Pathways
- Chronic Lymphocytic Leukemia Research
- Lymphoma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Acute Lymphoblastic Leukemia research
- Retinoids in leukemia and cellular processes
- Chronic Myeloid Leukemia Treatments
- Viral-associated cancers and disorders
- RNA modifications and cancer
- Cell death mechanisms and regulation
- Multiple Myeloma Research and Treatments
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- T-cell and Retrovirus Studies
- Hematopoietic Stem Cell Transplantation
- Ubiquitin and proteasome pathways
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- Nuclear Structure and Function
- Eosinophilic Disorders and Syndromes
- CNS Lymphoma Diagnosis and Treatment
- Immune Cell Function and Interaction
- Vector-Borne Animal Diseases
- Biochemical and Molecular Research
- Blood disorders and treatments
Kōchi University
2019-2024
Kochi Medical School Hospital
2023-2024
The University of Texas MD Anderson Cancer Center
2012-2023
Saga University
2013-2021
University of Alabama at Birmingham
2013
Leukemia Research Foundation
2013
Wakayama Medical University
2008-2009
Ehime University
2001-2007
Okayama University
1994-2005
La Roche College
2005
Abstract Although TP53 mutations are rare in acute myeloid leukemia (AML), inactivation of wild-type p53 protein frequently occurs through overexpression its negative regulator MDM2 (murine double minute 2). Recently, small-molecule antagonists MDM2, Nutlins, have been developed that inhibit the p53-MDM2 interaction and activate signaling. Here, we study effects activation by Nutlin-3 AML cells. Treatment with inhibitor triggered several molecular events consistent induction apoptosis: loss...
RG7112 is a small-molecule MDM2 antagonist. negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, phase I study patients with hematologic malignancies was conducted.Primary objectives included determination dose safety profile RG7112. Secondary evaluation pharmacokinetics; pharmacodynamics, such as TP53-mutation status expression; preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid...
The mitochondrial caseinolytic protease P (ClpP) plays a central role in protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the selectively kills cancer cells, independently p53 status, selective degradation its respiratory chain substrates disrupts structure function, while it does not affect non-malignant cells. We identified imipridones as potent activators ClpP. Through biochemical studies crystallography,...
ONC201 triggers an apoptotic cellular stress response in both solid and blood tumors.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 endocytic pathway. Here, we show that is released extracellular microvesicles (i.e. exosomes) from cells natively express LRRK2. localizes to collecting duct epithelial kidney actively secrete exosomes into urine. Purified urinary contain protein both dimerized and phosphorylated. We provide quantitative proteomic profile of 1673 proteins find...
Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause leukemias that refractory conventional treatment. The produces MLL/AF4 fusion protein activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show patient cells express high levels BCL-2 highly sensitive treatment with...
The nuclear transporter exportin‐1 ( XPO 1) is highly expressed in mantle cell lymphoma MCL ) cells, and believed to be associated with the pathogenesis of this disease. 1‐selective inhibitors export SINE compounds have been shown induce apoptosis cells. Given that p53 a cargo protein 1, we sought determine significance activation through 1 inhibition ‐induced We investigated prognostic impact expression cells using Oncomine analysis. mutational/functional status on sensitivity models...
Disease recurrence is the major problem in treatment of acute myeloid leukemia (AML). Relapse driven by stem cells, a chemoresistant subpopulation capable re-establishing disease. Patients with p53 mutant AML are at an extremely high risk relapse. B-cell-specific Moloney murine virus integration site 1 (BMI-1) required for self-renewal and maintenance cells. Here we studied effects novel small molecule inhibitor BMI-1, PTC596, Treatment PTC596 reduced MCL-1 expression triggered several...
AbstractDisruption of Mdm2-p53 interaction activates p53 signaling, disrupts the balance ofantiapoptotic and proapoptotic Bcl-2 family proteins induces apoptosis in acutemyeloid leukemia (AML). Overexpression may inhibit this effect. Thus,functional inactivation antiapoptotic enhance apoptogenic effects ofMdm2 inhibition. We here investigate potential therapeutic utility combinedtargeting Mdm2 by Nutlin-3a ABT-737, recently developed inhibitors ofprotein-protein interactions. ABT-737 induced...
The development of small-molecule activators p53 is currently focused on malignancies containing a wild-type genotype, which present in most leukemias. JNJ-26854165 one such p53-activating agent, but its mechanism action remains to be elucidated. Here, we report the effects acute treatment induced p53-mediated apoptosis leukemia cells with p53, rapidly drives transcription-independent followed by activation transcription-dependent pathway. accelerated proteasome-mediated degradation p21 and...
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells; however, not all wild-type TP53 tumors are sensitive to inhibition. Therefore, more potent and biomarkers predictive tumor sensitivity needed. The novel inhibitor DS-3032b is 10-fold than the first-generation nutlin-3a. mutations were resistance DS-3032b, allele frequencies negatively correlated with DS-3032b. However, varied greatly....
Herpesviruses frequently cause serious complications after allogeneic bone marrow transplantation (allo‐BMT). Recent studies have shown more rapid immune reconstitution peripheral blood stem cell (allo‐PBSCT) compared with allo‐BMT. However, it has not been clarified whether the improved allo‐PBSCT is associated a lower incidence of herpesvirus infections. We monitored emergence Epstein‐Barr virus (EBV), cytomegalovirus (CMV), human 6 (HHV‐6) and HHV‐7 DNA by nested‐double polymerase chain...
Abstract Activation of the Raf/MEK/ERK pathway and inactivation wild-type p53 by Mdm2 overexpression are frequent molecular events in acute myelogenous leukemia (AML). We investigated interaction pathways after their simultaneous blockades using a selective small-molecule antagonist Mdm2, Nutlin-3a, pharmacologic MEK-specific inhibitor, PD98059. found that PD98059, which itself has minimal apoptogenic activity, acts synergistically with Nutlin-3a to induce apoptosis AML cell lines OCI-AML-3...