Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12185-014-1580-4

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.immuni.2012.05.021.

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：International Journal of Hematology  

Congenital antithrombin (AT) or serpin C1 deficiency, caused by a SERPINC1 abnormality, is a high-risk factor for venous thrombosis. SERPINC1 is prone to genetic rearrangement, because it contains numerous Alu elements. In this study, a Japanese patient who developed deep vein thrombosis during pregnancy and exhibited low AT activity underwent SERPINC1 gene analysis using routine methods: long-range polymerase chain reaction (PCR) and real-time PCR. Sequencing using long-range PCR products revealed no pathological variants in SERPINC1 exons or exon–intron junctions, and all the identified variants were homozygous, suggesting a deletion in one SERPINC1 allele. Copy number quantification for each SERPINC1 exon using real-time PCR revealed half the number of exon 1 and 2 copies compared with controls. Moreover, a deletion region was deduced by quantifying the 5′-upstream region copy number of SERPINC1 for each constant region. Direct long-range PCR sequencing with primers for the 5'-end of each presumed deletion region revealed a large Alu-mediated deletion (∼13 kb) involving SERPINC1 exons 1 and 2. Thus, a large deletion was identified in SERPINC1 using conventional PCR methods.

DOI： 10.1007/s12185-024-03796-y

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Language：English   Publisher：Life Science Alliance  

Neurodegenerative diseases and other age-related disorders are closely associated with mitochondrial dysfunction. We previously showed that mice with neuron-specific deficiency of mitochondrial translation exhibit leukoencephalopathy because of demyelination. Reduced cholesterol metabolism has been associated with demyelinating diseases of the brain such as Alzheimer’s disease. However, the molecular mechanisms involved and relevance to the pathogenesis remained unknown. In this study, we show that inhibition of mitochondrial translation significantly reduced expression of the cholesterol synthase genes and degraded their sterol-regulated transcription factor, sterol regulatory element-binding protein 2 (Srebp2). Further-more, the phosphorylation of Pyk2 and Gsk3β was increased in the white matter of p32cKO mice. We observed that Pyk2 inhibitors reduced the phosphorylation of Gsk3β and that GSK3β inhibitors suppressed degradation of the transcription factor Srebp2. The Pyk2–Gsk3β axis is involved in the ubiquitination of Srebp2 and reduced expression of cholesterol gene. These results suggest that inhibition of mitochondrial translation may be a causative mechanism of neurodegenerative diseases of aging. Improving the mitochondrial translation or effectiveness of Gsk3β inhibitors is a potential therapeutic strategy for leukoencephalopathy.

DOI： 10.26508/lsa.202302423

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Language：English   Publisher：iScience  

Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are studied herein. Under glucose starvation, lysosomal protein expression decreased, leading to the accumulation of damaged lysosomes. Subsequently, cell death occurred via ferroptosis and iron accumulation due to DMT1 degradation. GPX4, a key factor in ferroptosis inhibition located on the outer membrane of lysosomes, accumulated in lysosomes, especially under glucose starvation, to protect cells from ferroptosis. ALDOA, GAPDH, NAMPT, and PGK1 are also located on the outer membrane of lysosomes and participate in lysosomal function. These enzymes did not function effectively under glucose starvation, leading to lysosomal dysfunction and ferroptosis. These findings may facilitate the treatment of lysosomal-related diseases.

DOI： 10.1016/j.isci.2024.109735

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Language：English   Publisher：Bioscience reports  

Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here, we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.

DOI： 10.1042/BSR20231992

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41409-023-02183-1

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms25073740

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1182/bloodadvances.2023010080

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/bioengineering10121437

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.15835

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

急性骨髄性白血病(AML)に特異的なミトコンドリア機能の制御に関与する分子メカニズムを検討した。CD34陽性AML細胞と健常な造血幹/前駆細胞を比較した代謝物スクリーニングを通じて、AMLにおけるリゾホスファチジン酸(LPA)合成活性の亢進を同定した。LPAは、LPA合成経路の律速酵素であるグリセロール-3-リン酸アシルトランスフェラーゼ(GPAT)によってグリセロール-3-リン酸から合成される。GPATの4つのアイソザイムのうち、グリセロール-3-リン酸アシルトランスフェラーゼ、ミトコンドリア(GPAM)がAML細胞で高発現していた。GPAMサイレンシングまたはFSG67(GPAM阻害剤)でLPA合成を阻害すると、ミトコンドリア分裂が誘導され、その結果、酸化的リン酸化が抑制され、活性酸素種が増加することで、AMLの増殖が著しく阻害された。さらに、FSG67によるGPAM阻害は、in vivoでの正常な造血に影響を与えることなく、AMLに対して有効であることが示された。以上より、GPAMを介したグリセロール-3-リン酸からのLPA合成経路は、AMLにおけるミトコンドリア動態を特異的に制御する重要な代謝機構であり、GPAMは有望な治療標的であることが示唆された。

Language：English   Publisher：Blood Advances  

Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia–specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), primary human acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) cells. Here, we show that human leukemia cells are addicted to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG), and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids, whose metabolic processes provide leukemia cells with critical substrates for the trichloroacetic acid cycle and the synthesis of nonessential amino acids, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates the function of the polycomb repressive complex 2, an epigenetic regulator for stem cell signatures, by inhibiting the transcription of PRC components, such as zeste homolog 2 and embryonic ectoderm development. Accordingly, BCAA catabolism plays an important role in the maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.

DOI： 10.1182/bloodadvances.2022008242

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Language：English   Publisher：Blood Advances  

The activation of β-catenin plays critical roles in normal stem cell function, and, when aberrantly activated, the maintenance and enhancement of cancer stemness in many solid cancers. Aberrant β-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast with such solid tumors. In this study, we showed that the AML-specific autocrine loop comprised of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of LSCs, independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL receptor–related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally active in immature LSCs compared with TIM-3–expressed differentiated AML blasts and exhausted T cells. These data suggest that human AML LSCs constitutively activates β-catenin via autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.

DOI： 10.1182/bloodadvances.2022008405

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41586-023-05834-x

Language：English   Publisher：International Journal of Hematology  

Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34+ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.

DOI： 10.1007/s12185-022-03458-x

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Language：English   Publisher：International Journal of Hematology  

Relapsed and refractory aggressive lymphoma have a poor prognosis. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is effective in chemosensitive patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is among the few options for non-chemosensitive patients. 18Fluoro-2-deoxy-d-glucose positron emission tomography–computed tomography (18FDG-PET/CT) is the standard tool for evaluating response to chemotherapy and residual tumor volume. However, accurate assessment of residual tumor volume is not currently being achieved in clinical practice, and its value in prognostic and therapeutic stratification remains unclear. To answer this question, we investigated the efficacy of quantitative indicators, including total metabolic tumor volume (TMTV), in predicting prognosis after auto-HSCT and allo-HSCT. We retrospectively analyzed 39 patients who received auto-HSCT and 28 who received allo-HSCT. In the auto-HSCT group, patients with a higher TMTV had a poor prognosis due to greater risk of relapse. In the allo-HSCT group, patients with a higher TMTV had a lower progression-free survival rate and a significantly higher relapse rate. Neither Deauville score nor other clinical parameters were associated with prognosis in either group. Therefore, pre-transplant TMTV on PET is effective for prognostic prediction and therapeutic decision-making for relapsed or refractory aggressive lymphoma.

DOI： 10.1007/s12185-022-03394-w

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Language：English   Publisher：International Journal of Hematology  

Prophylactic use of letermovir (LMV) markedly reduces the incidence of early clinically significant cytomegalovirus (csCMV) infection within the first 100 days after allogeneic hematopoietic cell transplantation (allo-HCT), which improves transplant outcomes. However, some patients eventually develop late-csCMV infection (beyond day 100) after completing LMV prophylaxis. To assess the incidence of late-csCMV infection as well as its risk factors and impacts on transplant outcome, a total of 81 allo-HCT recipients who had not developed early csCMV infection during LMV prophylaxis were retrospectively analyzed. Among them, 23 (28.4%) patients developed late-csCMV infection (until day 180) at a median time of 131 days after transplantation and 30 days after LMV discontinuation, respectively. Late-csCMV infection was correlated with apparent delayed immune reconstitution: patients transplanted from HLA-mismatched donors (hazard ratio [HR] = 13.0, p = 0.011) or CMV-IgG-negative donors (HR = 2.39, p = 0.043) had a significantly higher risk. In this study, transplant outcomes did not differ between patients with and without late-csCMV infection. This suggests a need to clarify the efficacy of extended administration of LMV for preventing late-csCMV infection in a larger number of allo-HCT recipients, especially those with “high-risk” donors.

DOI： 10.1007/s12185-022-03348-2

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.celrep.2022.110805

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1182/bloodadvances.2021004618

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12185-021-03191-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1182/bloodadvances

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12185-021-03207-6

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s42003-020-01463-6

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.isci.2020.101654

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English  

DOI： 10.1016/j.stem.2014.06.020

Language：English   Publishing type：Research paper (scientific journal)  

Event date： 2019.5

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Event date： 2016.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2016.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2015.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2015.9

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2015.7 - 2015.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：熊本   Country：Japan  

Event date： 2015.7

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2015.3

Language：English   Presentation type：Oral presentation (general)  

Country：United States  

Event date： 2014.11

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2014.10 - 2014.11

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2014.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都   Country：Japan  

Event date： 2014.9

Language：English   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Internal/External technical report, pre-print, etc.  

Language：English   Publishing type：Internal/External technical report, pre-print, etc.