35 results on '"Karigane D"'
Search Results
2. CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients
- Author
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Matsushita, M, primary, Ozawa, K, additional, Suzuki, T, additional, Nakamura, M, additional, Nakano, N, additional, Kanchi, S, additional, Ichikawa, D, additional, Matsuki, E, additional, Sakurai, M, additional, Karigane, D, additional, Kasahara, H, additional, Tsukamoto, N, additional, Shimizu, T, additional, Mori, T, additional, Nakajima, H, additional, Okamoto, S, additional, Kawakami, Y, additional, and Hattori, Y, additional
- Published
- 2017
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3. SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
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Watanuki S, Kobayashi H, Sugiura Y, Yamamoto M, Karigane D, Shiroshita K, Sorimachi Y, Morikawa T, Fujita S, Shide K, Haraguchi M, Tamaki S, Mikawa T, Kondoh H, Nakano H, Sumiyama K, Nagamatsu G, Goda N, Okamoto S, Nakamura-Ishizu A, Shimoda K, Suematsu M, Suda T, and Takubo K
- Subjects
- Animals, Mice, Cellular Senescence, Mice, Inbred C57BL, Glycolysis, Aging metabolism, Oxidative Stress, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells cytology, Mitochondria metabolism, Adenosine Triphosphate metabolism
- Abstract
Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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4. A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.
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Ediriwickrema A, Nakauchi Y, Fan AC, Köhnke T, Hu X, Luca BA, Kim Y, Ramakrishnan S, Nakamoto M, Karigane D, Linde MH, Azizi A, Newman AM, Gentles AJ, and Majeti R
- Abstract
Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to appropriately meet the biological demands of the human body. Human MPPs remain ill-defined whereas mouse MPPs have been well characterized with distinct immunophenotypes and lineage potencies. Using multiomic single cell analyses and complementary functional assays, we identified new human MPPs and oligopotent progenitor populations within Lin-CD34+CD38dim/lo adult bone marrow with distinct biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We show that within the canonical Lin-CD34+CD38dim/loCD90CD45RA-MPP population, there is a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69-erythroid-biased MPP. We also show that the canonical Lin-CD34+CD38dim/loCD90-CD45RA+ LMPP population can be separated into a CD2+ LMPP with lymphoid and myeloid potential, a CD2-LMPP with high lymphoid potential, and a CLL1+ GMP with minimal lymphoid potential. We used these new HSPC profiles to study human and mouse bone marrow cells and observe limited cell type specific homology between humans and mice and cell type specific changes associated with aging. By identifying and functionally characterizing new adult MPP sub-populations, we provide an updated reference and framework for future studies in human hematopoiesis.
- Published
- 2024
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5. Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells.
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Fowler JL, Zheng SL, Nguyen A, Chen A, Xiong X, Chai T, Chen JY, Karigane D, Banuelos AM, Niizuma K, Kayamori K, Nishimura T, Cromer MK, Gonzalez-Perez D, Mason C, Liu DD, Yilmaz L, Miquerol L, Porteus MH, Luca VC, Majeti R, Nakauchi H, Red-Horse K, Weissman IL, Ang LT, and Loh KM
- Subjects
- Animals, Humans, Mice, Endothelial Cells metabolism, Endothelial Cells cytology, Hematopoiesis, Homeodomain Proteins metabolism, Homeodomain Proteins genetics, Transcription Factors metabolism, Transcription Factors genetics, Basic-Leucine Zipper Transcription Factors genetics, Basic-Leucine Zipper Transcription Factors metabolism, Cell Differentiation, Cell Lineage, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells cytology, Pluripotent Stem Cells metabolism, Pluripotent Stem Cells cytology
- Abstract
The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (∼E8.5-E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate. We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies., Competing Interests: Declaration of interests Stanford University has filed patent applications related to blood and immune cell differentiation. J.L.F. is presently at Walking Fish Therapeutics, A.C. is presently at Orca Bio, and T.N. is presently at Century Therapeutics, but J.L.F., A.C., and T.N. contributed to this work while they were at Stanford University; none of these companies were involved in the present work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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6. Genome engineering with Cas9 and AAV repair templates generates frequent concatemeric insertions of viral vectors.
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Suchy FP, Karigane D, Nakauchi Y, Higuchi M, Zhang J, Pekrun K, Hsu I, Fan AC, Nishimura T, Charlesworth CT, Bhadury J, Nishimura T, Wilkinson AC, Kay MA, Majeti R, and Nakauchi H
- Abstract
CRISPR-Cas9 paired with adeno-associated virus serotype 6 (AAV6) is among the most efficient tools for producing targeted gene knockins. Here, we report that this system can lead to frequent concatemeric insertions of the viral vector genome at the target site that are difficult to detect. Such errors can cause adverse and unreliable phenotypes that are antithetical to the goal of precision genome engineering. The concatemeric knockins occurred regardless of locus, vector concentration, cell line or cell type, including human pluripotent and hematopoietic stem cells. Although these highly abundant errors were found in more than half of the edited cells, they could not be readily detected by common analytical methods. We describe strategies to detect and thoroughly characterize the concatemeric viral vector insertions, and we highlight analytical pitfalls that mask their prevalence. We then describe strategies to prevent the concatemeric inserts by cutting the vector genome after transduction. This approach is compatible with established gene editing pipelines, enabling robust genetic knockins that are safer, more reliable and more reproducible., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2024
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7. Context-dependent modification of PFKFB3 in hematopoietic stem cells promotes anaerobic glycolysis and ensures stress hematopoiesis.
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Watanuki S, Kobayashi H, Sugiura Y, Yamamoto M, Karigane D, Shiroshita K, Sorimachi Y, Fujita S, Morikawa T, Koide S, Oshima M, Nishiyama A, Murakami K, Haraguchi M, Tamaki S, Yamamoto T, Yabushita T, Tanaka Y, Nagamatsu G, Honda H, Okamoto S, Goda N, Tamura T, Nakamura-Ishizu A, Suematsu M, Iwama A, Suda T, and Takubo K
- Subjects
- Animals, Mice, Adenosine Triphosphate metabolism, Anaerobiosis, Hematopoiesis, Hematopoietic Stem Cells metabolism, Oxidative Phosphorylation, Phosphoric Monoester Hydrolases metabolism, Glycolysis, Phosphofructokinase-2 genetics, Phosphofructokinase-2 metabolism
- Abstract
Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in murine HSCs and elucidate their regulatory mechanisms. Through quantitative
13 C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of ATP levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression of Pfkfb3 induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss of Pfkfb3 suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells., Competing Interests: SW, HK, YS, MY, DK, KS, YS, SF, TM, SK, MO, AN, KM, MH, ST, TY, TY, YT, GN, HH, SO, NG, TT, AN, MS, AI, TS, KT No competing interests declared, (© 2023, Watanuki, Kobayashi et al.)- Published
- 2024
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8. IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.
- Author
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Landberg N, Köhnke T, Feng Y, Nakauchi Y, Fan AC, Linde MH, Karigane D, Lim K, Sinha R, Malcovati L, Thomas D, and Majeti R
- Abstract
Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia., Significance: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma., (©2023 American Association for Cancer Research.)
- Published
- 2024
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9. IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.
- Author
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Landberg N, Köhnke T, Feng Y, Nakauchi Y, Fan AC, Linde MH, Karigane D, Lim K, Sinha R, Malcovati L, Thomas D, and Majeti R
- Abstract
Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC Class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent development and relapse of leukemia.
- Published
- 2023
- Full Text
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10. Simplified Intrafemoral Injections Using Live Mice Allow for Continuous Bone Marrow Analysis.
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Nakauchi Y, Ediriwickrema A, Martinez-Krams D, Zhao F, Rangavajhula A, Karigane D, and Majeti R
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- Humans, Animals, Mice, Prospective Studies, Hematopoietic Stem Cells, Bone Marrow Cells, Hematopoiesis, Bone Marrow Transplantation, Bone Marrow, Hematopoietic Stem Cell Transplantation methods
- Abstract
Despite the complexity of hematopoietic cell transplantation in humans, researchers commonly perform intravenous or intrafemoral (IF) injections in mice. In murine models, this technique has been adapted to enhance the seeding efficiency of transplanted hematopoietic stem and progenitor cells (HSPCs). This paper describes a detailed step-by-step technical procedure of IF injection and the following bone marrow (BM) aspiration in mice that allows for serial characterization of cells present in the BM. This method enables the transplantation of valuable samples with low cell numbers that are particularly difficult to engraft by intravenous injection. This procedure facilitates the creation of xenografts that are critical for pathological analysis. While it is easier to access peripheral blood (PB), the cellular composition of PB does not reflect the BM, which is the niche for HSPCs. Therefore, procedures providing access to the BM compartment are essential for studying hematopoiesis. IF injection and serial BM aspiration, as described here, allow for the prospective retrieval and characterization of cells enriched in the BM, such as HSPCs, without sacrificing the mice.
- Published
- 2023
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11. RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition.
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Fan AC, Nakauchi Y, Bai L, Azizi A, Nuno KA, Zhao F, Köhnke T, Karigane D, Cruz-Hernandez D, Reinisch A, Khatri P, and Majeti R
- Subjects
- Humans, Gene Expression Regulation, Signal Transduction, Core Binding Factor Alpha 2 Subunit genetics, Interleukin-3 genetics, Interleukin-3 pharmacology, Leukemia drug therapy, Leukemia genetics
- Abstract
Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood, and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we used primary patient samples and a RUNX1-KO model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the IL-3 receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1-KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable targeting of these aggressive blood cancers with existing agents.
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- 2023
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12. Distinct roles of the preparatory and payoff phases of glycolysis in hematopoietic stem cells.
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Shiroshita K, Kobayashi H, Watanuki S, Karigane D, Sorimachi Y, Tamaki S, Haraguchi M, Yamamoto M, Nakamura-Ishizu A, Okamoto S, Kataoka K, and Takubo K
- Subjects
- Oxidative Phosphorylation, Pentose Phosphate Pathway genetics, Adenosine Triphosphate metabolism, Hematopoietic Stem Cells metabolism, Glycolysis genetics
- Abstract
In physiological conditions, most adult hematopoietic stem cells (HSCs) maintain a quiescent state. Glycolysis is a metabolic process that can be divided into preparatory and payoff phases. Although the payoff phase maintains HSC function and properties, the role of the preparatory phase remains unknown. In this study, we aimed to investigate whether the preparatory or payoff phases of glycolysis were required for maintenance of quiescent and proliferative HSCs. We used glucose-6-phosphate isomerase (Gpi1) as a representative gene for the preparatory phase and glyceraldehyde-3-phosphate dehydrogenase (Gapdh) as a representative gene for the payoff phase of glycolysis. First, we identified that stem cell function and survival were impaired in Gapdh-edited proliferative HSCs. Contrastingly, cell survival was maintained in quiescent Gapdh- and Gpi1-edited HSCs. Gapdh- and Gpi1-defective quiescent HSCs maintained adenosine-triphosphate (ATP) levels by increasing mitochondrial oxidative phosphorylation (OXPHOS), whereas ATP levels were decreased in Gapdh-edited proliferative HSCs. Interestingly, Gpi1-edited proliferative HSCs maintained ATP levels independent of increased OXPHOS. Oxythiamine, a transketolase inhibitor, impaired proliferation of Gpi1-edited HSCs, suggesting that the nonoxidative pentose phosphate pathway (PPP) is an alternative means to maintain glycolytic flux in Gpi1-defective HSCs. Our findings suggest that OXPHOS compensated for glycolytic deficiencies in quiescent HSCs, and that in proliferative HSCs, nonoxidative PPP compensated for defects in the preparatory phase of glycolysis but not for defects in the payoff phase. These findings provide new insights into regulation of HSC metabolism, which could have implications for development of novel therapies for hematologic disorders., Competing Interests: Conflict of Interest Disclosure The authors do not have any conflicts of interest to declare in relation to this work., (Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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13. A culture platform to study quiescent hematopoietic stem cells following genome editing.
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Shiroshita K, Kobayashi H, Watanuki S, Karigane D, Sorimachi Y, Fujita S, Tamaki S, Haraguchi M, Itokawa N, Aoyoama K, Koide S, Masamoto Y, Kobayashi K, Nakamura-Ishizu A, Kurokawa M, Iwama A, Okamoto S, Kataoka K, and Takubo K
- Subjects
- Animals, Mice, Humans, Cytokines metabolism, Gene Editing methods, Hematopoietic Stem Cells
- Abstract
Other than genetically engineered mice, few reliable platforms are available for the study of hematopoietic stem cell (HSC) quiescence. Here we present a platform to analyze HSC cell cycle quiescence by combining culture conditions that maintain quiescence with a CRISPR-Cas9 genome editing system optimized for HSCs. We demonstrate that preculture of HSCs enhances editing efficiency by facilitating nuclear transport of ribonucleoprotein complexes. For post-editing culture, mouse and human HSCs edited based on non-homologous end joining and cultured under low-cytokine, low-oxygen, and high-albumin conditions retain their phenotypes and quiescence better than those cultured under the proliferative conditions. Using this approach, HSCs regain quiescence even after editing by homology-directed repair. Our results show that low-cytokine culture conditions for gene-edited HSCs are a useful approach for investigating HSC quiescence ex vivo ., (© 2022 The Authors.)
- Published
- 2022
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14. The Cell Type-Specific 5hmC Landscape and Dynamics of Healthy Human Hematopoiesis and TET2-Mutant Preleukemia.
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Nakauchi Y, Azizi A, Thomas D, Corces MR, Reinisch A, Sharma R, Cruz Hernandez D, Köhnke T, Karigane D, Fan A, Martinez-Krams D, Stafford M, Kaur S, Dutta R, Phan P, Ediriwickrema A, McCarthy E, Ning Y, Phillips T, Ellison CK, Guler GD, Bergamaschi A, Ku CJ, Levy S, and Majeti R
- Subjects
- Azacitidine pharmacology, Chromatin genetics, DNA-Binding Proteins genetics, Hematopoiesis genetics, Humans, Proto-Oncogene Proteins genetics, Dioxygenases genetics, Myelodysplastic Syndromes, Preleukemia
- Abstract
The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis., Significance: We show that 5-hydroxymethylation profiles are cell type-specific and associated with transcriptional abundance and chromatin accessibility across human hematopoiesis. TET2 loss caused aberrant growth and differentiation phenotypes and disrupted 5hmC and transcriptional landscapes. Treatment of TET2 KO HSPCs with ascorbate or azacitidine reverted 5hmC profiles and restored aberrant phenotypes. This article is highlighted in the In This Issue feature, p. 265., (©2022 American Association for Cancer Research.)
- Published
- 2022
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15. Mitf is required for T cell maturation by regulating dendritic cell homing to the thymus.
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Karigane D, Haraguchi M, Toyama-Sorimachi N, Nishimura EK, and Takubo K
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- Animals, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, Cell Differentiation genetics, Cells, Cultured, Dendritic Cells metabolism, Flow Cytometry, Gene Expression Regulation immunology, Hyperplasia, Integrin alpha4 genetics, Integrin alpha4 immunology, Integrin alpha4 metabolism, Mice, Inbred C57BL, Mice, Knockout, Microphthalmia-Associated Transcription Factor genetics, Microphthalmia-Associated Transcription Factor metabolism, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes metabolism, Thymus Gland metabolism, Thymus Gland pathology, Mice, Cell Differentiation immunology, Dendritic Cells immunology, Microphthalmia-Associated Transcription Factor immunology, T-Lymphocytes immunology, Thymus Gland immunology
- Abstract
Thymic dendritic cells (DCs) promote immune tolerance by regulating negative selection of autoreactive T cells in the thymus. How DC homing to the thymus is transcriptionally regulated is still unclear. Microphthalmia-associated transcription factor (Mitf) is broadly expressed and plays essential roles in the hematopoietic system. Here, we used Mitf-mutated mice (Mitf
vit/vit ) and found enlargement of the thymus and expansion of CD4/CD8 double-positive T cells. Mitf was highly expressed in a subset of thymic DCs among the hematopoietic system. Genetic mutation or pharmacological inhibition of Mitf in DCs decreased the expression levels of Itga4, which are critical molecules for the homing of DCs to the thymus. Further, inhibition of Mitf decreased thymic DC number. These results suggest a pivotal role of Mitf in the maintenance of T cell differentiation by regulating the homing of DC subsets within the thymus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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16. Detection of residual disease in chronic myeloid leukemia utilizing genomic next generation sequencing reveals persistence of differentiated Ph + B cells but not bone marrow stem/progenitors.
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Karigane D, Kasahara H, Shiroshita K, Fujita S, Kobayashi H, Tamaki S, Yamazaki R, Yahagi K, Yatabe Y, Kondoh N, Arai T, Katagiri H, Shimizu N, Sakurai M, Kikuchi T, Kato J, Shimizu T, Hayakawa T, Yaguchi T, Matsushita M, Nakajima H, Kawakami Y, Murata M, Mori T, Sasaki T, Okamoto S, and Takubo K
- Subjects
- B-Lymphocytes, Genomics, High-Throughput Nucleotide Sequencing, Humans, Neoplasm, Residual genetics, Protein Kinase Inhibitors therapeutic use, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Persistence of leukemic stem cells (LSCs) results in the recurrence of chronic myeloid leukemia (CML) after the administration of tyrosine kinase inhibitors (TKIs). Thus, the detection of minimal residual disease (MRD) with LSC potential can improve prognosis. Here, we analyzed 115 CML patients and found that CD25 was preferentially expressed on the phenotypic stem and progenitor cells (SPCs), and TKI therapy decreased the number of CD25-positive cells in the SPC fraction. To detect MRD harboring BCR-ABL1 fusion DNA, we developed a highly-sensitive method using patient-specific primers and next-generation sequencing. By using this method, we identified that in patients who achieved molecular remission, almost all residual CD25-positive SPCs were BCR-ABL1 -negative. Moreover, in some patients BCR-ABL1 was detectable in peripheral B cells but not in SPCs. We conclude that CD25 marks LSCs at diagnosis but does not mark MRD following TKI treatment and that analysis of peripheral B cells can allow sensitive detection of MRD.
- Published
- 2021
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17. p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts.
- Author
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Sorimachi Y, Karigane D, Ootomo Y, Kobayashi H, Morikawa T, Otsu K, Kubota Y, Okamoto S, Goda N, and Takubo K
- Subjects
- Aging metabolism, Animals, Ataxia Telangiectasia Mutated Proteins physiology, Cell Proliferation, Female, Hematopoiesis, Hematopoietic Stem Cells cytology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Reactive Oxygen Species metabolism, Aging pathology, Cell Differentiation, Cellular Senescence, Hematopoietic Stem Cells metabolism, Mitogen-Activated Protein Kinase 14 physiology
- Abstract
Hematopoietic stem cells (HSCs) and their progeny sustain lifetime hematopoiesis. Aging alters HSC function, number, and composition and increases risk of hematological malignancies, but how these changes occur in HSCs remains unclear. Signaling via p38 mitogen-activated kinase (p38MAPK) has been proposed as a candidate mechanism underlying induction of HSC aging. Here, using genetic models of both chronological and premature aging, we describe a multimodal role for p38α, the major p38MAPK isozyme in hematopoiesis, in HSC aging. We report that p38α regulates differentiation bias and sustains transplantation capacity of HSCs in the early phase of chronological aging. However, p38α decreased HSC transplantation capacity in the late progression phase of chronological aging. Furthermore, codeletion of p38α in mice deficient in ataxia-telangiectasia mutated, a model of premature aging, exacerbated aging-related HSC phenotypes seen in ataxia-telangiectasia mutated single-mutant mice. Overall, these studies provide new insight into multiple functions of p38MAPK, which both promotes and suppresses HSC aging context dependently., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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18. Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells.
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Nishimura T, Xu H, Iwasaki M, Karigane D, Saavedra B, Takahashi Y, Suchy FP, Monobe S, Martin RM, Ohtaka M, Nakanishi M, Burrows SR, Cleary ML, Majeti R, Shibuya A, and Nakauchi H
- Subjects
- Animals, Apoptosis, Caspase 9 genetics, Caspase 9 metabolism, Cell Differentiation, Cell Line, Humans, Mice, Induced Pluripotent Stem Cells metabolism, Pluripotent Stem Cells metabolism
- Abstract
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have promising potential for opening new avenues in regenerative medicine. However, since the tumorigenic potential of undifferentiated pluripotent stem cells (PSCs) is a major safety concern for clinical transplantation, inducible Caspase-9 (iC9) is under consideration for use as a fail-safe system. Here, we used targeted gene editing to introduce the iC9 system into human iPSCs, and then interrogated the efficiency of inducible apoptosis with normal iPSCs as well as diseased iPSCs derived from patients with acute myeloid leukemia (AML-iPSCs). The iC9 system induced quick and efficient apoptosis to iPSCs in vitro. More importantly, complete eradication of malignant cells without AML recurrence was shown in disease mouse models by using AML-iPSCs. In parallel, it shed light on several limitations of the iC9 system usage. Our results suggest that careful use of the iC9 system will serve as an important countermeasure against posttransplantation adverse events in stem cell transplantation therapies.
- Published
- 2019
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19. Renal dysfunction and anemia associated with long-term imatinib treatment in patients with chronic myelogenous leukemia.
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Sakurai M, Kikuchi T, Karigane D, Kasahara H, Matsuki E, Hashida R, Yamane Y, Abe R, Koda Y, Toyama T, Kato J, Shimizu T, Yokoyama Y, Suzuki S, Nakamura T, Okamoto S, and Mori T
- Subjects
- Adult, Aged, Female, Follow-Up Studies, Hemoglobins metabolism, Humans, Male, Middle Aged, Retrospective Studies, Time Factors, Anemia blood, Anemia chemically induced, Anemia epidemiology, Imatinib Mesylate administration & dosage, Imatinib Mesylate adverse effects, Kidney Diseases blood, Kidney Diseases chemically induced, Kidney Diseases epidemiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology
- Abstract
Knowledge of the toxicity profile of long-term treatment with imatinib is limited. In the present study, we sought to evaluate renal function and hemoglobin levels during long-term imatinib treatment. Eighty-two patients with chronic myelogenous leukemia in chronic phase who had been on imatinib for over 5 years were retrospectively analyzed. The mean estimated glomerular filtration rate (eGFR) was significantly decreased over 5 years (77 ± 17 to 62 ± 14 ml/min/1.73m², P < 0.001). Higher age and lower eGFR value at initiation of imatinib were significantly associated with development of renal dysfunction by multivariate analyses. Mean hemoglobin levels also significantly decreased over the 5-year period (12.9 ± 1.7 to 12.4 ± 1.3 g/dl, P < 0.01). The rate of decrease in eGFR correlated significantly with hemoglobin levels (correlation coefficient = - 0.249, P < 0.05). Serum erythropoietin (EPO) levels did not increase in 16 patients with both renal dysfunction and anemia (median, 31.9 mIU/ml). In patients who participated in a clinical trial of imatinib discontinuation, mean eGFR (50.0 ± 6.5 to 56.0 ± 10.2 ml/min/1.73m², P < 0.05) and hemoglobin levels (12.0 ± 1.7 to 14.0 ± 1.6 g/dl, P < 0.01) improved significantly at 1 year after discontinuation. These findings suggest that long-term imatinib results in a partially reversible continuous decline in renal function and decreased hemoglobin levels.
- Published
- 2019
- Full Text
- View/download PDF
20. Geriatric screening tools predict survival outcomes in older patients with diffuse large B cell lymphoma.
- Author
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Sakurai M, Karigane D, Kasahara H, Tanigawa T, Ishida A, Murakami H, Kikuchi M, and Kohashi S
- Subjects
- Age Factors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Doxorubicin analogs & derivatives, Female, Humans, Kaplan-Meier Estimate, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Male, Mass Screening methods, Prednisolone administration & dosage, Prognosis, Retrospective Studies, Rituximab administration & dosage, Treatment Outcome, Vincristine administration & dosage, Geriatric Assessment, Lymphoma, Large B-Cell, Diffuse mortality
- Abstract
The proportion of elderly patients with diffuse large B cell lymphoma (DLBCL) appears to be increasing, with outcomes varying widely because of the patients' heterogeneity. Geriatric assessment is used to predict prognosis in elderly patients with DLBCL, but the utility of two simple screening tools for patients with DLBCL, the Flemish version of the Triage Risk Screening Tool (fTRST) and G8, has remained to be elucidated. We retrospectively assessed patients using fTRST and G8, and evaluated the impacts of the scores on survival outcomes in older patients with newly diagnosed DLBCL. A total of 59 patients aged 65 years or older and who were diagnosed with DLBCL were included. The median age was 77 years (range, 65-91 years), and the initial treatments were R-CHOP (63%) and R-THPCOP (31%). The estimated 2-year overall survival (OS) rate was significantly lower in patients with abnormal fTRST scores (≥ 2; N = 17) than in those with normal fTRST scores (< 2; N = 42): (50.5% (95% CI, 22.7-73.0%) vs. 82.2% (95% CI, 63.8-91.8%), P = 0.007). The estimated 2-year OS rate was significantly lower also in patients with abnormal G8 scores (≤ 14; N = 38) than in those with normal G8 scores (> 14; N = 21): (66.1% (95% CI, 46.7-79.5%) vs. 86.8% (95% CI, 55.7-96.7%), P = 0.03, respectively). These associations were independently significant after adjusting for other significant factors by multivariate analysis. These results suggest that the easy-to-use geriatric screening tools, fTRST and G8, have strong prognostic value for OS in older patients with DLBCL.
- Published
- 2019
- Full Text
- View/download PDF
21. Invasive hepatic mucormycosis: A case report and review of the literature.
- Author
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Karigane D, Kikuchi T, Sakurai M, Kato J, Yamane Y, Hashida R, Abe R, Hatano M, Hasegawa N, Wakayama M, Shibuya K, Okamoto S, and Mori T
- Subjects
- Aged, Amphotericin B administration & dosage, Amphotericin B therapeutic use, Antifungal Agents administration & dosage, Antifungal Agents therapeutic use, Autopsy, Fatal Outcome, Ferritins blood, Galactose analogs & derivatives, Humans, Invasive Fungal Infections blood, Invasive Fungal Infections drug therapy, Liver Diseases diagnosis, Liver Diseases drug therapy, Male, Mannans blood, Mucormycosis blood, Mucormycosis drug therapy, Primary Myelofibrosis blood, Primary Myelofibrosis complications, Primary Myelofibrosis drug therapy, Spleen pathology, Invasive Fungal Infections complications, Liver Diseases microbiology, Mucormycosis complications
- Abstract
Mucormycosis generally develops under immunocompromised conditions, including hematological malignancies and solid organ or hematopoietic stem cell transplantation. Although mucormycosis usually affects the lungs and paranasal sinuses, sporadic cases of invasive mucormycosis of the liver have been reported. We hereby report a patient with myelofibrosis who developed hepatic mucormycosis diagnosed by post-mortem examination. An extensive literature review identified 13 reported cases of hepatic mucormycosis, including ours, without lung involvement. Most of the underlying diseases or conditions were hematological malignancies and solid organ transplantation. Three cases had splenic lesions and four had gastrointestinal lesions, suggesting the possibility of translocation to the liver and/or spleen from the gastrointestinal tracts. Hepatic mucormycosis should be recognized as one of the presentations of invasive mucormycosis, especially when hepatic nodules are found in immunocompromised patients such as those with hematological malignancy or recipients of solid organ transplantation., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
22. Very Late Relapse of Acute Promyelocytic Leukemia 17 Years after Continuous Remission.
- Author
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Sakurai M, Watanuki S, Kato J, Hashida R, Yamane Y, Karigane D, Mitsuhashi T, Murata M, Ueno H, Nakazato T, Okamoto S, and Mori T
- Subjects
- Antineoplastic Agents therapeutic use, Chronic Disease, Humans, Male, Middle Aged, Prognosis, Recurrence, Risk Factors, Time Factors, Treatment Outcome, Leukemia, Promyelocytic, Acute drug therapy, Remission Induction methods, Tretinoin therapeutic use
- Abstract
The prognosis of acute promyelocytic leukemia (APL) has been improved by the combination of all-trans retinoic acid (ATRA) with chemotherapy. Nonetheless, relapse occurs in a certain proportion of patients, mostly within three to four years after treatment. We herein report a patient treated with ATRA and chemotherapy achieving remission who relapsed approximately 17 years after the treatment. A literature review identified 5 additional reported cases of APL relapse after more than 10 years. None of them presented with generally established risk factors for relapse, such as a high leukocyte count. The potential for late relapse of APL occurring more than 10 years after treatment should be recognized.
- Published
- 2018
- Full Text
- View/download PDF
23. Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography with gallium-67 scintigraphy in the initial clinical staging of diffuse large B-cell lymphoma.
- Author
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Sakurai M, Toyama T, Kikuchi T, Kato J, Shimizu T, Koda Y, Karigane D, Yamane Y, Abe R, Yamazaki R, Nakazato T, Nakahara T, Jinzaki M, Okamoto S, and Mori T
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Lymphoma, B-Cell pathology, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Neoplasm Staging, Retrospective Studies, Young Adult, Fluorine Radioisotopes, Fluorodeoxyglucose F18, Gallium Radioisotopes, Lymphoma, B-Cell diagnostic imaging, Lymphoma, Large B-Cell, Diffuse diagnostic imaging, Positron-Emission Tomography, Radionuclide Imaging, Radiopharmaceuticals
- Abstract
Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been recommended as a complementary tool for the staging of various malignancies, including malignant lymphoma. PET findings often shift patients to higher stages and may affect treatment outcomes. In this study, we retrospectively compared staging and treatment outcomes of newly diagnosed diffuse large B-cell lymphoma (DLBCL) assessed by PET (n = 153) or gallium-67 scintigraphy (Ga) (n = 95). In total, Ga upstaged two (2.1%) of 95 patients, whereas PET upstaged 13 (8.5%) of 153 patients. Bone/bone marrow (15 vs. 4%, P = 0.01) and muscle lesion (5 vs. 0%, P = 0.03) were identified more frequently in the PET group than in the Ga group. The estimated 3-year overall and progression-free survival rates did not differ significantly in the two groups at any stage. However, patients with stage III disease tended to have better progression-free survival in the PET group than in the Ga group [92.3 (95% CI 56.6-98.9%) vs. 58.3% (95% CI 27.0-80.1%), P = 0.086]. These results suggest that PET has a greater potential in detecting musculoskeletal lesions of DLBCL as extranodal lesions than Ga, and may contribute to the optimal staging.
- Published
- 2018
- Full Text
- View/download PDF
24. [Mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment].
- Author
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Watanuki S, Kikuchi T, Toyama T, Abe R, Nakayama H, Karigane D, Shimizu T, Kikuchi J, Matsumoto K, Yasuoka H, Kataoka M, Okamoto S, and Mori T
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dasatinib therapeutic use, Female, Humans, Treatment Outcome, Dasatinib adverse effects, Hypertension, Pulmonary chemically induced, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Mixed Connective Tissue Disease chemically induced
- Abstract
A 37-year-old woman was diagnosed with chronic phase chronic myeloid leukemia. Nilotinib treatment was initiated; however, it had to be discontinued due to an allergic reaction one month later, and dasatinib treatment was provided. Although favorable response was obtained, she started complaining of shortness of breath 7 months after initiating dasatinib treatment. Chest X-ray and echocardiography indicated pulmonary congestion and hypertension. Further, she was diagnosed with mixed connective tissue disease (MCTD) based on Raynaud phenomenon, swollen fingers, sclerodactyly, pancytopenia, hypocomplementemia, and positive anti-U1-RNP antibody. Consequently, dasatinib treatment was discontinued, and she was administered prednisolone (1 mg/kg/day), which was effective and successfully tapered with concomitant administration of cyclophosphamide. This is the first case of MCTD that developed during dasatinib treatment. However, because the present case was a young woman, the development of MCTD could probably be attributed to autoimmune diatheses or it may be a coincidence. However, the possibility of patients receiving dasatinib treatment developing autoimmune diseases needs to be assessed.
- Published
- 2018
- Full Text
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25. Successful treatment of breakthrough disseminated Trichosporon asahii fungemia in a patient with acute myeloid leukemia receiving itraconazole prophylaxis.
- Author
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Karigane D, Sakurai M, Matsuyama E, Ide K, Yamamoto-Takeuchi S, Inazumi T, and Kohashi S
- Abstract
We encountered a case of a 73-year-old man with acute myeloid leukemia who developed Trichosporon asahii systemic infection while on itraconazole prophylaxis during severe neutropenia. Cryptococcal antigen was useful for diagnosis. Although itraconazole was ineffective in protecting against trichosporonosis, treatment was successful with voriconazole following liposomal amphotericin B.
- Published
- 2017
- Full Text
- View/download PDF
26. Effects of calcineurin inhibitors on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation.
- Author
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Saburi M, Kohashi S, Kato J, Koda Y, Sakurai M, Toyama T, Kikuchi T, Karigane D, Yuda S, Yamane Y, Hashida R, Abe R, Nakazato T, Hirahashi J, Ogata M, Okamoto S, and Mori T
- Subjects
- Adolescent, Adult, Aged, Calcineurin Inhibitors administration & dosage, Cyclosporine administration & dosage, Female, Humans, Male, Middle Aged, Retrospective Studies, Tacrolimus administration & dosage, Young Adult, Allografts, Calcineurin Inhibitors adverse effects, Cyclosporine adverse effects, Hematopoietic Stem Cell Transplantation, Kidney Diseases chemically induced, Sodium metabolism, Tacrolimus adverse effects
- Abstract
Calcineurin inhibitors (CIs) such as cyclosporine A (CSA) and tacrolimus often cause renal dysfunction, resulting in increased serum creatinine, hyperkalemia, and hyperuricemia. However, the effects of CIs on sodium excretion have not been fully elucidated. We retrospectively evaluated the effects of CI administration on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Fifty consecutive recipients each of allogeneic HSCT receiving either CSA or tacrolimus (100 patients in total) with available data for weekly fractional excretion of sodium (FENa) for a 4-week period after transplantation were enrolled in this retrospective analysis. No significant differences in patient characteristics were observed between CSA and tacrolimus groups except for the type of donor. FENa was significantly higher at the 3rd (1.25 ± 0.80) and 4th weeks (1.53 ± 1.06) after transplantation as compared with that at the 1st week (0.93 ± 0.51; P < 0.01, P < 0.001, respectively) in the tacrolimus group, but not at any time point in the CSA group. In addition, FENa was significantly higher in the tacrolimus group than the CSA group at the 4th week (1.53 ± 1.06 vs. 1.13 ± 0.80; P < 0.05). These results suggest that tacrolimus increases sodium excretion after allogeneic HSCT, and that this effect is minimal with CSA.
- Published
- 2017
- Full Text
- View/download PDF
27. Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions.
- Author
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Karigane D and Takubo K
- Subjects
- Adipocytes metabolism, Animals, Cell Differentiation, Citric Acid Cycle, Epigenesis, Genetic, Fatty Acids metabolism, Gene Expression Regulation, Leukemic, Glycolysis, Hematopoiesis, Hematopoietic Stem Cells cytology, Humans, Hypoxia metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Ketone Oxidoreductases metabolism, Leukemia genetics, Nucleic Acids metabolism, Oxidative Phosphorylation, Resting Phase, Cell Cycle, Energy Metabolism, Hematopoietic Stem Cells metabolism, Homeostasis, Leukemia metabolism, Neoplastic Stem Cells metabolism, Stress, Physiological
- Abstract
Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.
- Published
- 2017
- Full Text
- View/download PDF
28. Allogeneic hematopoietic stem cell transplantation following treatment with brentuximab vedotin for refractory Hodgkin lymphoma.
- Author
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Yamane Y, Koda Y, Kohashi S, Kato J, Hashida R, Sakurai M, Toyama T, Kikuchi T, Okayama M, Kasahara H, Karigane D, Shimizu T, Okamoto S, and Mori T
- Subjects
- Adult, Brentuximab Vedotin, Female, Humans, Male, Recurrence, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation, Hodgkin Disease therapy, Immunoconjugates therapeutic use
- Abstract
Brentuximab vedotin (BV) is a novel agent used for the treatment of relapsed or refractory Hodgkin lymphoma. We have described two patients with refractory Hodgkin lymphoma, who were successfully treated with BV followed by allogeneic hematopoietic stem cell transplantation (HSCT). Although both patients were resistant to conventional chemotherapies, they responded to four or five doses of BV given every 3 weeks. Then, the patients underwent bone marrow transplantation from unrelated donors after reduced-intensity conditioning consisting of fludarabine and melphalan. They remained progression-free for more than 3 years after the transplantation. These findings suggest that BV could be a promising bridging therapy to curative allogeneic HSCT for relapsed or refractory Hodgkin lymphoma. Further accumulation of such cases is warranted to evaluate the efficacy and safety of BV therapy prior to allogeneic HSCT.
- Published
- 2017
- Full Text
- View/download PDF
29. p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress.
- Author
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Karigane D, Kobayashi H, Morikawa T, Ootomo Y, Sakai M, Nagamatsu G, Kubota Y, Goda N, Matsumoto M, Nishimura EK, Soga T, Otsu K, Suematsu M, Okamoto S, Suda T, and Takubo K
- Subjects
- Animals, Apoptosis, Cell Proliferation, Enzyme Activation, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells enzymology, IMP Dehydrogenase antagonists & inhibitors, IMP Dehydrogenase metabolism, Mice, Inbred C57BL, Microphthalmia-Associated Transcription Factor metabolism, Mutation genetics, Phenotype, Reactive Oxygen Species metabolism, Cell Cycle, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Purines metabolism, Stress, Physiological, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. We do not yet have a clear understanding of how this metabolic activity changes during stress hematopoiesis, such as bone marrow transplantation. Here, we report a critical role for the p38MAPK family isoform p38α in initiating hematopoietic stem and progenitor cell (HSPC) proliferation during stress hematopoiesis in mice. We found that p38MAPK is immediately phosphorylated in HSPCs after a hematological stress, preceding increased HSPC cycling. Conditional deletion of p38α led to defective recovery from hematological stress and a delay in initiation of HSPC proliferation. Mechanistically, p38α signaling increases expression of inosine-5'-monophosphate dehydrogenase 2 in HSPCs, leading to altered levels of amino acids and purine-related metabolites and changes in cell-cycle progression in vitro and in vivo. Our studies have therefore uncovered a p38α-mediated pathway that alters HSPC metabolism to respond to stress and promote recovery., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
30. Unfavorable outcome of chronic myelogenous leukemia in adolescent and young adults treated with tyrosine kinase inhibitors.
- Author
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Sakurai M, Mori T, Karigane D, Tozawa K, Matsuki E, Shimizu T, Yokoyama K, Nakajima H, Kanda Y, and Okamoto S
- Subjects
- Adolescent, Adult, Aged, Asian People, Disease-Free Survival, Female, Follow-Up Studies, Humans, Japan epidemiology, Male, Middle Aged, Survival Rate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects
- Abstract
Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the outcome of chronic myelogenous leukemia in the chronic phase (CML-CP). However, one study has reported a less favorable treatment outcome with TKIs in adolescents and young adults (AYA) when compared with older patients. In the present study, we retrospectively reviewed the response to TKIs in a Japanese population of 133 CML-CP patients divided into an AYA group (n = 19) and an older group (n = 114). At diagnosis, AYA patients presented with higher white blood cell counts and lower percentage of basophils, and with lower Hasford scores, but no difference was observed in EUTOS score. Probability of achieving complete cytogenetic response was not statistically different between the groups. However, the probabilities of achieving major and complete molecular responses were significantly lower in the AYA group compared to the older group (61 vs 87 % and 17 vs. 33 % at 24 months, respectively; P < 0.05). In addition, a 7-year event-free survival was significantly lower in the AYA compared to the older adults (58 vs. 80 %, P < 0.05). These results suggest that AYA Japanese patients with CML-CP tend to have an unfavorable outcome on treatment with TKI.
- Published
- 2015
- Full Text
- View/download PDF
31. Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING.
- Author
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Kobayashi H, Kobayashi CI, Nakamura-Ishizu A, Karigane D, Haeno H, Yamamoto KN, Sato T, Ohteki T, Hayakawa Y, Barber GN, Kurokawa M, Suda T, and Takubo K
- Subjects
- Animals, Bacteria metabolism, Bacteria pathogenicity, Cyclic GMP administration & dosage, Cyclic GMP immunology, Cyclic GMP metabolism, Gene Expression Regulation, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells microbiology, Interferon Regulatory Factor-3 immunology, Membrane Proteins immunology, Mice, Signal Transduction drug effects, Signal Transduction immunology, Stem Cell Niche immunology, Transforming Growth Factor beta genetics, Transforming Growth Factor beta immunology, Cyclic GMP analogs & derivatives, Hematopoietic Stem Cells metabolism, Immunity, Innate, Interferon Regulatory Factor-3 genetics, Membrane Proteins genetics
- Abstract
Upon systemic bacterial infection, hematopoietic stem and progenitor cells (HSPCs) migrate to the periphery in order to supply a sufficient number of immune cells. Although pathogen-associated molecular patterns reportedly mediate HSPC activation, how HSPCs detect pathogen invasion in vivo remains elusive. Bacteria use the second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) for a variety of activities. Here, we report that c-di-GMP comprehensively regulated both HSPCs and their niche cells through an innate immune sensor, STING, thereby inducing entry into the cell cycle and mobilization of HSPCs while decreasing the number and repopulation capacity of long-term hematopoietic stem cells. Furthermore, we show that type I interferon acted as a downstream target of c-di-GMP to inhibit HSPC expansion in the spleen, while transforming growth factor-β was required for c-di-GMP-dependent splenic HSPC expansion. Our results define machinery underlying the dynamic regulation of HSPCs and their niches during bacterial infection through c-di-GMP/STING signaling., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
32. Toxic epidermal necrolysis in the absence of circulating T cells: a possible role for resident memory T cells.
- Author
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Iriki H, Adachi T, Mori M, Tanese K, Funakoshi T, Karigane D, Shimizu T, Okamoto S, and Nagao K
- Subjects
- Antigens, CD analysis, Antigens, Differentiation, T-Lymphocyte analysis, Cerebral Hemorrhage complications, Fatal Outcome, Humans, Immunologic Memory, Lectins, C-Type analysis, Leukocyte Common Antigens analysis, Male, Middle Aged, Stevens-Johnson Syndrome complications, Stevens-Johnson Syndrome drug therapy, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Stevens-Johnson Syndrome immunology
- Published
- 2014
- Full Text
- View/download PDF
33. Cytomegalovirus enteritis in immunocompetent subjects: a case report and review of the literature.
- Author
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Karigane D, Takaya S, Seki Y, Mastumoto Y, Onose A, Kosakai A, Sugaya N, and Mori T
- Subjects
- Aged, Female, Humans, Cytomegalovirus Infections etiology, Enteritis etiology
- Abstract
Cytomegalovirus (CMV) enteritis (or colitis) is generally diagnosed in immunocompromised patients in association with human immunodeficiency virus infection as well as in recipients of solid organ or hematopoietic stem cell transplant. CMV enteritis has been reported only sporadically in immunocompetent individuals. We encountered a 76-year-old woman who developed CMV enteritis without any previously identified immunocompromised states. An extensive literature review of 33 cases of CMV enteritis or colitis diagnosed in immunocompetent individuals, including the present case, revealed that the median age of the patients was 68, the accompanying symptoms were diarrhea (76%), abdominal pain (52%), and hematochezia or melena (27%), and that the outcome was generally favorable, including resolution without any treatment in 24% of the patients. CMV enteritis should be recognized more widely as a disease entity not only in immunocompromised patients but also in immunocompetent individuals, especially in elderly populations., (Copyright © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
34. [Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug-induced lymphocyte stimulation test].
- Author
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Shimizu T, Mori T, Karigane D, Kikuchi T, Koda Y, Toyama T, Nakajima H, and Okamoto S
- Subjects
- Fatal Outcome, Humans, Leukemia drug therapy, Male, Middle Aged, Myelodysplastic Syndromes drug therapy, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury immunology, Drug Hypersensitivity etiology, Drug Hypersensitivity immunology, Hydroxyurea adverse effects, Hydroxyurea immunology, Immunologic Tests methods, Lymphocyte Activation immunology
- Abstract
A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.
- Published
- 2014
35. [Early diagnosis of metastatic spinal tumor is a key for effective palliative radiotherapy in patients with lung cancer].
- Author
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Isono H, Kemmoku T, Nakamura Y, Onose A, Matsumoto Y, Watanabe R, Haraguchi M, Kasajima M, Takaya S, Ishihara M, Karigane D, and Nagata H
- Subjects
- Aged, Early Detection of Cancer, Fatal Outcome, Humans, Male, Spinal Cord Neoplasms diagnosis, Spinal Cord Neoplasms secondary, Lung Neoplasms pathology, Palliative Care, Spinal Cord Neoplasms radiotherapy
- Abstract
Patients with metastatic spinal tumor are the largest in number among the patients with bone tumor. It causes a severe bone pain, pathological fracture and spinal cord compression. Thus it harshly hampers patient's quality of life. We report 3 patients with lung cancer whose initial manifestation was metastatic spinal tumor. We treated the 3 patients with palliative radiotherapy and medication. Although the severe pain has improved on a numerical rating scale(NRS), but performance status(PS)and activity of daily living(ADL)of the 3 patients got worse because the disease was progressed and complicated. Generally, PS of cancer patients found by bone matastasis is low. However, it is difficult to take an effective treatment, which leads to ADL improvement. There are many choices for treating metastatic bone tumors including pain control, bisphosphonate administration, radiation therapy, strontium radiotherapy, bone cement, palliative surgery and orthotics. In addition, a development of molecular target drugs, such as Denosmab, is expected as future modality of palliative care. In conclusion, we should detect a bone metastasis in the patient with lung cancer as early as possible, and select an appropriate treatment in collaboration with each specialist for achieving the ADL and PS improvement.
- Published
- 2011
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