Publications by authors named "Kazuhito Naka"

TGF-β is an immunosuppressive cytokine and plays a key role in progression of cancer by inducing immunosuppression in tumor microenvironment. Therefore, inhibition of TGF-β signaling pathway may provide a potential therapeutic intervention in treating cancers. Herein, we report the discovery of a series of novel thiazole derivatives as potent inhibitors of ALK5, a serine-threonine kinase which is responsible for TGF-β signal transduction.

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Article Synopsis
  • A significant percentage of patients with acute myeloid leukemia (AML) relapse after standard chemotherapy, highlighting the need for more effective treatments.
  • Researchers developed a new anticancer drug, (R)-WAC-224 (R-WAC), which targets topoisomerase II and has shown strong anti-leukemia effects in lab tests.
  • R-WAC demonstrated less toxicity compared to traditional drugs like doxorubicin and improved survival in animal models, especially when combined with cytarabine, suggesting it could be a valuable new option for AML therapy.
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The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand breaks (DSBs) at the BCR gene located on chromosome 9q34 and the ABL1 gene located on chromosome 22q11. Thus, mimicking the initiation process of translocation, we induced CRISPR/Cas9-mediated DSBs simultaneously at the breakpoints of the BCR and ABL1 genes in a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent human leukemia cell line.

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In this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation.

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The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'.

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Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy.

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It is well known that mature chronic myelogenous leukemia (CML) cells proliferate in response to oncogenic BCR-ABL1-dependent signaling, but how CML stem cells are able to survive in an oncogene-independent manner and cause disease relapse has long been elusive. Here, I put into the context of the broader literature our recent finding that lysophospholipid metabolism is essential for the maintenance of CML stem cells. I describe the fundamentals of lysophospholipid metabolism and discuss how one of its key enzymes, Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3), is responsible for maintaining the unique characteristics of CML stem cells.

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Chronic myelogenous leukemia (CML) stem cells are the cellular source of the vast majority of mature CML cells and responsible for relapse of CML disease post-tyrosine kinase inhibitor (TKI) therapy. Although mature CML cells, whose active division is driven by BCR-ABL1 oncogene-dependent signaling, are reduced by TKI therapy, CML stem cells are resistant because they become quiescent via a heretofore elusive mechanism that is independent of oncogene signaling. Recent advances in highly sensitive metabolomics analyses, however, have unveiled new metabolic pathways that are essential for the survival of CML stem cells.

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Article Synopsis
  • 5-Fluorouracil (5-FU) is commonly used to treat colorectal cancer, but drug resistance, often due to cancer stem cells, poses significant treatment challenges.
  • The study identifies the KHDRBS3 gene as a potential contributor to 5-FU resistance, revealing higher expression levels in KRAS-mutant cancer cells and a correlation between KHDRBS3 positivity and poorer patient prognosis.
  • The research suggests that KHDRBS3 aids in maintaining stem cell properties, which enhances drug resistance and tumor growth, making it a promising marker for predicting chemotherapy outcomes in colorectal cancer patients.
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  • 5-FU is a critical drug for treating gastric cancer, but cancer stem cells (CSCs) contribute to drug resistance, complicating treatment.
  • Researchers developed gastric cancer organoids (GCOs), exposed them to increasing levels of 5-FU, and identified four 5-FU-resistant organoids with altered expression of 5-FU metabolism-related molecules.
  • The study highlighted KHDRBS3 as a potential prognostic marker in gastric cancer, linking it to stem cell-like traits, multi-drug resistance, and a better understanding of treatment responses in patients receiving 5-FU chemotherapy.
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Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show that disruption of the Gdpd3 gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that Gdpd3 deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells.

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Article Synopsis
  • The study focuses on Uc.63+, a type of long non-coding RNA, and its potential role in gastric cancer (GC) progression, which had not been previously explored in this context.
  • Researchers measured Uc.63+ levels in GC patient samples and found that higher Uc.63+ expression was linked to more severe cancer features and enhanced cell growth/migration in lab experiments.
  • The findings suggest that Uc.63+ promotes GC progression by influencing cell dynamics through the activation of NF-κB signaling pathways.
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Therapeutic strategies that target leukemic stem cells (LSCs) provide potential advantages in the treatment of chronic myeloid leukemia (CML). Here, we show that selective blockade of plasminogen activator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSCs to tyrosine kinase inhibitor (TKI), which facilitates the eradication of CML-LSCs and leads to sustained remission of the disease. We demonstrated for the first time that TGF-β-PAI-1 axis was selectively augmented in CML-LSCs in the bone marrow (BM), whereby protecting CML-LSCs from TKI treatment.

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Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy.

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Leukemia stem cells (LSCs) are responsible for relapse of leukemia. LSCs maintain their self-renewal capacity, stemness properties, and therapeutic resistance in a manner dependent on their cell of origin and genetic alterations acquired during subsequent clonal evolution. Specific mechanisms of metabolic control and nutrient acquisition are implicated in the regulation of LSC survival.

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Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members.

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Throughout the lifetime of an individual, hematopoietic stem cells (HSCs) maintain the homeostasis of normal hematopoiesis through the precise generation of mature blood cells. Numerous genetic studies in mice have shown that stem-cell quiescence is critical for sustaining primitive long-term HSCs in vivo. In this review, we first examine the crucial roles of transforming growth factor β (TGF-β) and related signaling molecules in not only regulating the well-known cytostatic effects of these molecules but also governing the self-renewal capacity of HSCs in their in vivo microenvironmental niche.

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Traditionally, the intracellular localization and expression levels of specific proteins in CML Leukemia stem cells (LSCs) have been evaluated by fluorescence immunohistochemistry (FIHC). More recently, Duolink(®) in situ PLA technology has opened up a new and more quantitative way to evaluate signal transduction, posttranslational modification, and protein-protein interaction at the single-stem-cell level. This novel methodology, which employs two antibody-based probes, has already increased our understanding of the biology of the rare CML LSC population.

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Although the discovery of tyrosine kinase inhibitors (TKIs) has dramatically improved the prognoses of chronic myelogenous leukemia (CML) patients, a cure has remained elusive. Unanswered questions include how long must a patient continue on TKI therapy, and how does a patient know when he/she can safely stop or finish this therapy? Imagawa et al. have carefully addressed these questions of safety and efficacy using a stop study of the second-generation TKI dasatinib.

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Geminin regulates chromatin remodeling and DNA replication licensing which play an important role in regulating cellular proliferation and differentiation. Transcription of the Geminin gene is regulated via an E2F-responsive region, while the protein is being closely regulated by the ubiquitin-proteasome system. Our objective was to directly transduce Geminin protein into cells.

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Dipeptide species are accumulated in the chronic myelogenous leukemia (CML) stem cells [1]. To investigate the molecular mechanisms of the accumulation of dipeptide species in CML stem cells, we performed transcriptome sequencing of long-term stem cells, short-term stem cells, progenitor cells from healthy control and CML-affected mice (GSE70031). The transcriptome data revealed that the expression of a dipeptide transporter (solute carrier family 15, member 2 (SLC15A2)) was elevated only in the CML stem cells.

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Background: IL-10-producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10 cells share overlapping phenotypic markers with CD5 B1 B cells, CD1dCD21CD23 marginal zone (MZ) B cells, and CD1dCD21CD23 T2-MZ precursor B cells but do not exclusively belong to either subset.

Objective: In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10 cells.

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Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia-initiating cells (CML-LICs). However, little is known about the therapeutic benefits such CML-LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW-7197, an orally bioavailable transforming growth factor-β signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML-LICs in vivo.

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Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques.

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Cancer stem cells are the cellular sources of the vast majority of mature cancer cells and are reportedly responsible for the recurrence of disease following anti-cancer therapy. Recent advantages in the cancer stem cell research field have indicated that TGF-β signaling pathway plays an essential role for the maintenance of cancer stem cells via regulating cancer stemness, quiescence, epithelial -mesenchymal transition (EMT), or therapeutic resistance in vivo. Therefore, the outcome of these investigations will hopefully be the development of novel agents that can specifically control both augmentation and suppression of TGF-β signaling pathway in cancer stem cells, and thereby provide a novel avenue for curative cancer patient therapy.

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