Arinobu Tojo

The Institute of Medical Science, The University of Tokyo · Division of Molecular Therapy

Human T‐cell Lymphotropic Virus Type 1 (HTLV‐1) is traditionally linked to severe conditions such as adult T‐cell leukemia/lymphoma, HTLV‐1‐associated myelopathy, and HTLV‐1 uveitis, with vertical transmission, particularly mother to child thorough breastfeeding, considered the primary route. Despite efforts to reduce vertical transmission through...

Introduction Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflamma...

Background In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Methods We conducted a post-marketing all-case surveillance...

Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1–7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targetin...

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics ana...

Introduction Transposable elements (TEs) are widely spread across the human genome. Although TEs have been implicated in the pathogenesis of hematological malignancies, their expression in myelodysplastic syndromes (MDS) has not yet received extensive analysis. In the present study, we performed RNA sequence analysis of bone marrow stem and progeni...

Introduction Ponatinib inhibits the BCR::ABL1 kinase, including a variant with threonine-to-isoleucine at position 315 (T315I) (Cortes et al. N Eng J Med. 2013; 369:1783-96); however, it has been reported that ponatinib is associated with a higher risk of major arterial events than other TKIs among patients with CML, those with a resistance/intoler...

The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancest...

Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3−/− mice was shown to depend on Toll-like...

Gene editing using engineered nucleases frequently produces unintended genetic lesions in hematopoietic stem cells (HSCs). Gene-edited HSC cultures thus contain heterogeneous populations, the majority of which either do not carry the desired edit or harbor unwanted mutations. In consequence, transplanting edited HSCs carries the risks of suboptimal...

Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+ CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis...

Background: Cancer immunotherapy is an effective way of battling cancer, and is based on artificial stimulation of the immune system to attack cancer cells. Although several strategies show successful results, it remains to prevent the subsequent cancer escape from the immune surveillance. The further success depends on a variety of functional effe...

Cancer pain is a significant issue in terminally ill cancer patients (TICPs). The fentanyl patch (FP) is used extensively for treating cancer pain, but FP requirements vary between patients. We aimed to identify determinants of FP requirements in TICPs and propose effective pain relief using a FP. In a retrospective chart review, we investigated ca...

(1) Objectives: The effect of cell-processing protocols on the clinical efficacy of bone tissue engineering is not well-known. To maximize efficacy, we optimized the cell-processing protocol for bone-marrow-derived mesenchymal stromal cells for bone tissue engineering. In this study, the efficacy of bone tissue engineering using this modified proto...

Introduction Mesenchymal stromal cells (MSCs) hold the potential for application as cellular therapy products; however, there are many problems that need to be addressed before the use in clinical settings, these include the heterogeneity of MSCs, scalability in MSC production, timing and techniques for MSC administration, and engraftment efficienc...

We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional deletion of Hoip led to significantly longer survival and marked depletion of leukemia burden in...

SLC29A3, also known as ENT3, is a lysosomal transmembrane protein that transports nucleosides from the lysosomes to the cytoplasm ¹ . Loss-of-function mutations in SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs 2,3 . However, little is known about the mechanism through which lysosomal nucleos...

During aging, hematopoietic stem cells (HSCs) alter quantitatively and qualitatively. Aged HSCs show attenuated repopulation activity and abnormal differentiation. However, the alterations in heterogeneity of HSCs with aging remain unknown. In this study, we performed single-cell RNA sequence (scRNA-seq) analysis of HSCs from young (10 weeks old),...

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with differen...

Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are distinct entities of blood neoplasms, and the exact developmental origin of both neoplasms are considered be heterogenous among patients. However, reports of concurrent LCH and AML are rare. Herein we report a novel case of concurrent LCH and AML which shared same the driver m...

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by sustained mature neutrophilic leukocytosis. Recently, presence of colony-stimulating factor 3 receptor (CSF3R) mutations has been added to the diagnostic criteria for CNL. Anti-inflammatory effects of the JAK1/2 inhibitor ruxolitinib relieve constitutio...

Strategies integrating activation of innate and adaptive immunity against cancer are desired. We established a novel platform, Wilms’ tumor antigen 1 (WT1)-expressing artificial adjuvant vector cells (aAVC-WT1), linking invariant natural killer T (iNKT)-mediated dendritic cell activation to T cell immunity. Here, we report the first-in-human applic...

Even though hematopoietic stem cell transplantation (HSCT) allows successful treatment for many malignant and non-malignant disorders, its curative potential remains limited by severe side effects, including infections and other transplant-related complications such as graft-versus-host disease (GvHD). This study examined changes in serum proteome...

This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twi...

Severe congenital neutropenia (SCN) is characterized by severe neutropenia and recurrent critical infections. X-linked neutropenia (XLN) is caused by a gain-of-function mutation in the Wiskott-Aldrich syndrome gene (WAS), the product of which (WASp) is expressed only in blood cells, especially during neutrophil maturation. To investigate the mechan...

The identification of characteristic differences between cancer stem cells and their normal counterparts remains a key challenge for cancer treatment. Here, we investigated the role of immunoglobulin superfamily member 8 (Igsf8, also known as EWI-2, PGRL, and CD316) on normal and malignant hematopoietic stem cells, mainly using the conditional knoc...

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and frequent progression to leukemia. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space. Despite several studies impl...

Background: The breakthrough effects of tyrosine kinase inhibitors (TKIs) have lessened indications for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia (CML). However, HSCT is still attractive for children and adolescents/young adults (AYAs) requiring lifelong TKI therapy. Nevertheless, little has been reporte...

HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Recent studies have addressed se...

Lineage switches in acute leukemia occur rarely, and the underlying mechanisms are poorly understood. Herein, we report the case of an elderly patient with leukemia in which the leukemia started as B-cell acute lymphoblastic leukemia (B-ALL) and later changed to B- and T-cell mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) du...

Gene editing using engineered nucleases frequently produces on- and off-target indels in hematopoietic stem cells (HSCs). Gene-edited HSC cultures thus contain genetically heterogenous populations, the majority of which either do not carry the desired edit or harbor unwanted mutations. In consequence, transplanting edited HSCs carries the risks of...

We present a case of a 41-year-old woman who was diagnosed with autoimmune polyendocrine syndrome type 1 (APS-1) at the age of 2. She developed severe anemia and was diagnosed with pure red cell aplasia (PRCA) and T-cell large granular lymphocyte leukemia at the age of 34. The pathogenesis of APS-1 is based on the presence of an inactive mutation i...

Histiocytosis is a syndrome characterized by fever, pain, and other symptoms caused by the neoplastic proliferation of atypical cells of the macrophage-dendritic cell lineage and surrounding inflammatory cell infiltration. The diagnosis is confirmed by the immune-histological features of biopsied specimens. From this viewpoint, histiocytosis is div...

Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our in...

Acute myeloid leukemia (AML) relapse is considered to be related to escape from antitumor immunity. Changes in the expression of immune checkpoints, including B7 homolog (H)1 and B7-H2, have been reported to contribute to AML progression. Binding of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) among other...

Background Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patien...

Background: Although bone tissue engineering for dentistry has been studied for many years, the clinical outcome for severe cases has not been established. Furthermore, there are limited numbers of studies that include long-term follow-up. In this study, the safety and efficacy of bone tissue engineering for patients with a severely atrophic alveo...

Ubiquitination is a post-translational modification that plays important roles in the regulation of various cellular processes. The linear ubiquitin chain assembly complex (LUBAC) is the only E3 ubiquitin ligase, which can specifically generate linear ubiquitin chains. LUBAC is composed of three subunits: catalytic Hoip (Rnf31), Hoil-1l (RBCK1), an...

Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying on...

Significance Human breast cancer develops after a long period of latency under premalignant conditions. Strategies to target the premalignant conditions have yet to materialize since the molecular mechanisms remain obscure. Here, we discovered that FRS2β, expressed in a subset of mammary epithelial cells, directly activates nuclear factor–κB (NF-κB...

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our...

Objectives Patients with hematological cancer receiving chemotherapy have a high risk of thiamine deficiency due to accelerated thiamine usage by tumor cells. Mild or severe thiamine deficiency can lead to varying degrees of neurological symptoms. We evaluated the relationship between thiamine deficiency and neurological symptoms, including mild or...

Background Clinical evidence of thiamine-related neuropsychiatric symptoms, including the initial stage, is limited because serum thiamine levels tend to be evaluated only for patients who develop severe neuropsychiatric symptoms suspected to be related to severe thiamine deficiency. This study aimed to evaluate the relationship between thiamine de...

Mesenchymal stromal cells (MSCs) are known to have immunosuppressive ability and have been used in clinical treatment of acute graft-versus-host disease, one of severe complications of the hematopoietic stem cell transplantation. However, MSCs are activated to suppress the immune system only after encountering an inflammatory stimulation. Thus, it...

The polymerase chain reaction-based open reading frame typing (POT) method is a simple and rapid method for the strain-level discrimination of methicillin-resistant Staphylococcus aureus (MRSA). We investigated the molecular charac- teristics of S. aureus strains by multilocus sequencing typing (MLST) and POT and the profiles of antibiotic resistan...

Chronic inflammation is a hallmark of HIV infection and is associated with the development and progression of age-related comorbidities. Although the gastrointestinal tract is a major site of HIV replication and CD4 ⁺ T-cell depletion, the role of HIV-associated imbalance of gut microbiome in chronic inflammation is unclear.

During aging, hematopoietic stem cells (HSCs) alter quantitatively as well as qualitatively. Aged HSCs show attenuated repopulation activity and abnormal differentiation such as myeloid-biased differentiation. However, the alterations in heterogeneity of HSCs with aging remain largely unknown. In this study, we performed single-cell RNA sequence (s...

Background Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatmen...

p>It is widely held that pro-inflammatory changes often precede the onset of breast cancer. However, the underlying molecular mechanisms are largely unknown. Here, we demonstrate that FRS2β, a membrane-linked adaptor protein expressed in a small subset of luminal epithelial cells, triggers the inflammatory changes in precancerous mammary tissues an...

Unrelated bone marrow transplantation (uBMT) is performed to treat blood disorders, and it uses bone marrow from an unrelated donor as the transplant source. Although the importance of HLA matching in uBMT has been established, that of other genetic factors, such as single-nucleotide polymorphisms (SNPs), remains unclear. The application of immunoi...

Introduction The appearance of erythroblasts (EBLs) in peripheral blood occurs in a variety of serious conditions and has been associated with mortality in critically ill patients. However, the incidence, risk factor, and outcomes of EBLs after cord blood transplantation (CBT) remain unclear. Methods We have investigated the impact of EBLs on tran...

Introduction After the first appearance of peripheral blood neutrophils, recipients from adult donor sources have a rapid increase in neutrophil recovery, whereas cord blood transplantation (CBT) recipients have a slow increase. However, the momentum of neutrophil recovery after CBT varies widely among individuals, but optimal methods to evaluate t...

Cord blood transplantation (CBT) has major limitations, including delayed hematopoietic recovery and a higher incidence of graft failure in adult patients. The necessary conditioning intensity depends on the graft source, and higher‐intensity conditioning regimens can provide sufficient immunosuppression to prevent graft failure.

Simple Summary In recent years, next-generation sequencing has become a major tool in the management of cancer, advancing the diagnosis and treatment of hematological malignancies. However, the gold standard for cancer diagnosis and monitoring still involves invasive and painful procedures, such as tissue and bone marrow biopsies. These procedures...

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase 1,2 . ABL1 -selective tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML 3–7 . The ultimate goal of CML treatment is likely to be TKI-free maintenance of deep molecular response (DMR...

Background Peripheral blood eosinophilia has been associated with the development of graft-versus-host disease (GVHD) and survival after allogeneic hematopoietic cell transplantation (HCT). However, the impacts of eosinophilia on cord blood transplantation (CBT) outcomes remain unclear. Objectives To examine the associations between eosinophilia a...

Cancer stem‐like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c‐Myc expression induces stronger DNA replication stress in patient‐derived breast CSC...

A prior history of cancer was associated with higher non-relapse mortality or overall mortality in patients undergoing allogeneic haematopoietic cell transplantation. Because it is unclear whether the outcomes after cord blood transplantation are influenced by a prior history of cancer, we retrospectively assessed the prevalence and prognostic impa...

Although classic Hodgkin's lymphoma (CHL) sometimes develops after treatment for multiple myeloma (MM), simultaneous diagnosis of both malignancies is extremely rare without previous treatment history. Here we describe a case of a 54-year-old female who complained of left cervical lymphadenopathy. Biopsy specimen from the left cervical lymph node r...

In personalized cancer genomic medicine, characterizing a patient’s molecular profile based on comprehensive information is important for maximizing treatment benefits. However, current cancer genome analysis is centered on single nucleotide variation (SNV), gene expression, and copy number variation (CNV) but places little emphasis on structural v...

Background: Multiple myeloma (MM) patients may undergo relapse and experience resistance to existing therapies. Cereblon (CRBN) is key mediator of the bioactivities of immunomodulatory drugs (IMiDs), including lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and considered to contribute to IMiD re...

Myelodysplastic syndromes (MDS) is a clonal disorder of hematopoietic stem cells (HSCs) characterized by clonal hematopoietic stem cells (HSCs) with cytopenia, morphological abnormalities, genetic alteration, ineffective normal hematopoiesis, and frequent progression to AML. It has long remained unresolved how MDS cells, which are less proliferativ...

Immunoglobulin superfamily member 8 (IGSF8, also known as EWI-2, PGRL, and CD316), is a cell surface protein containing 4 immunoglobulin domains. IGSF8 directly binds to the tetraspanin molecules, CD9 and CD81, and modulates cell adhesion, migration, and growth. Previous studies demonstrated that IGSF8 was associated with prognosis and metastasis i...

Introduction: Myeloid/Natural killer (NK) cell precursor acute leukemia (MNKPL) is a rare hematologic malignancy prevalent in East Asia. MNKPL is characterized by extramedullary involvement, immature lymphoblastoid morphology without myeloperoxidase (MPO) reactivity, the CD7+/CD33+/CD34+/CD56+/HLA−DR+ phenotype. MNKPL is classified as mixed phenoty...

Severe congenital neutropenia (SCN) is characterized by severe neutropenia and recurrent episodes of critical infections. X-linked neutropenia (XLN) is a very rare type of SCN caused by a gain-of-function mutation in the Wiscott-Aldrich syndrome gene (WAS), the product of which (WASp) is expressed only in blood cells, and especially to higher exten...

Vancomycin (VCM) is frequently used for neutropenic patients undergoing cord blood transplantation (CBT). We retrospectively examined the relationship between VCM trough levels and the efficacy and toxicity in 122 adult patients undergoing CBT in our institute. The median initial dose of VCM based on body weight was 9.1 mg/kg/dose (range, 6.0–22.6...

Background:Recent progress in chemotherapy has prolonged the survival of patients with hematological diseases, but has also increased the number of patients with chemotherapy-related cardiac dysfunction (CTRCD). However, the causes of individual variations and risk factors for CTRCD have yet to be fully elucidated. Methods and Results:Consecutive e...