The introduction of new agents and hematopoietic stem cell transplantation into the treatment of ATL has activated its clinical research. However, the prognosis of ATL remains poor compared with those of other leukemias and lymphomas. Thus, seemingly we have to reconsider a new strategy of ATL therapy based on its unique characteristics. HTLV-1 infection of T cells results in clonal proliferation of infected cells that accumulate genetic and epigenetic abnormalities before the onset of ATL. Therefore, the treatment strategy should include the prevention of HTLV-1 infection and ATL development in addition to precision medicine based on the stratification of ATL cases by biomarkers that discriminate clinical stages of ATL. I summarize here the recent progress in ATL research focusing on the biomolecular abnormalities that lead to clonal expansion and malignant transformation of HTLV-1-infected T cells. Apparently, one of the bases for the prevention of ATL is to establish a disease entity of "chronic active HTLV-1 infection" that defines high-risk carriers for ATL development and enables preventive intervention.

Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations. Current treatment approaches are not curative for CLL, except allogeneic hematopoietic stem cell transplantation, which is rarely offered to the majority of patients aged 70 years and older. Currently, there is no evidence that the initiation of therapy for asymptomatic early-stage disease improves the overall survival, even for patients with high-risk disease. The identification that the B-cell receptor (BCR) signaling pathway is aberrantly and constitutively activated in CLL has recently led to the development of BCR signaling inhibitors, ibrutinib and idelalisib. In addition, a novel BCL-2 antagonist, venetoclax, appears promising when used alone or in combination with anti-CD20 antibodies. The advent of novel small-molecule inhibitors has revolutionized the treatment approaches for patients with CLL.

Myelodysplastic syndrome (MDS) is a group of clonal disorders affecting hematopoietic stem cells. Thus, the only potential curative therapy is hematopoietic stem cell transplantation (HSCT). Indeed, for high-risk patients with MDS, who have a higher anticipated risk of leukemic transformation and shorter survival, HSCT is the first choice for eligible patients. DNA hypomethylating agents, the only agents proved to prolong survival, are used in non-HSCT-eligible high-risk patients with MDS. In contrast, due to high transplant-related mortality rate, treatment strategies other than HSCT are mainly applied for the low-risk group with expected long-term survival. Lately, treatment options, including the progress of supportive therapy, for low-risk patients with MDS have increased. The availability of the treatment options that enhance QOL and prolong survival is the need of the present time. This review will discuss the outline of such treatment strategies, especially for low-risk patients with MDS.

Aplastic anemia is a syndrome in which hematopoietic stem cells are decreased and bone marrow hypoplasia and pancytopenia are observed; it is considered as a T cell-mediated autoimmune disease. Recently, it has been reported that gene mutations suggestive of clonal hematopoiesis are detected in approximately one third of the patients with aplastic anemia. Among treatment approaches other than hematopoietic stem cell transplantation, immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporin is a basic approach, although it has been shown that eltrombopag, a thrombopoietin receptor agonist, is effective and that the recovery of hematopoiesis in three blood lineage is observed in some patients. Studies on the optimum dose of ATG are in progress. Regarding hematopoietic stem cell transplantation for aplastic anemia, regimens are being designed in which cyclophosphamide as a pretreatment is reduced and fludarabine is instead used in combination for the reduction of cardiotoxicity. Because HLA haploidentical transplantation has been developed and its reports are increasing for patients who cannot find appropriate donors, transplantation may be possible in patients who had previously given up on it.

During steady-state conditions, hematopoietic stem cells (HSCs) maintain a quiescent status in the cell cycle. Upon infection or inflammation, bone marrow HSCs begin proliferating and generating differentiated hematopoietic cells via multi-lineage differentiation and self-renewal; this effect is partially due to the alteration of their surrounding microenvironment or niche. In addition, recent studies have revealed that the bone marrow niche critically contributes to abnormal hematopoiesis, including leukemogenesis. In this review, we discuss the recent advances in our understanding of HSC/niche functions and the regulatory machineries employed during homeostasis, stress hematopoiesis, or disease conditions.

Hematopoietic stem cells (HSCs) have the potential to self-renew and differentiate into multi-lineage mature hematopoietic cells; thus, these cells can maintain hematopoiesis. Human HSCs reside within the CD34+CD38- cell fractions. Similarly, in acute myelogenous leukemia (AML), a small number of leukemic cells, called leukemic stem cells (LSCs), can be enriched within the identical CD34+CD38- cell fractions. LSCs can self-renew and produce clonogenic leukemic cells, whereas non-LSCs lack the potential to self-renew or maintain leukemia; thus, AML is organized as a hierarchy that originated from LSCs. LSCs play a central role in the maintenance and progression of leukemia; therefore, these cells should be an ultimate target for the eradication of human AML. Previous studies have revealed specific molecular machineries essential for LSCs. Targeting LSC-specific molecules should be a good therapeutic approach to kill LSCs without affecting normal cells. In this review, we would like to introduce the recent progress in the LSC study.

Leukemia stem cells (LSCs) are responsible for relapse of leukemia. LSCs maintain their self-renewal capacity, stemness properties, and therapeutic resistance in a manner dependent on their cell of origin and genetic alterations acquired during subsequent clonal evolution. Specific mechanisms of metabolic control and nutrient acquisition are implicated in the regulation of LSC survival. Recent advances in gene modification strategies in mice and in sophisticated metabolomics technologies are producing novel inquiries in LSC research performed in vivo. In this review, I examined our current knowledge on the roles of various metabolic pathways, including glucose metabolism, lipid oxidation, and an alternative route of amino acid and peptide supply, that support the maintenance of self-renewal capacity and therapeutic resistance in LSCs in vivo.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by impaired hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Epigenetic regulators, including TET2, DNMT3A and EZH2, are often mutated in patients with MDS. Recently, exome sequencing of blood cells from aged people without hematological malignancies have demonstrated the presence of clonal hematopoiesis with myeloid malignancies-associated mutations, such as TET2 and DNMT3A. Here, I will discuss the molecular mechanisms underlying the accumulation of epigenetic alterations and genetic mutations, including TET2, DNMT3A and EZH2, and how these promote the development of MDS and hematological malignancies in aged people with clonal hematopoiesis.

With the aim of evaluating the safety and efficacy of filgrastim biosimilar 1(Filgrastim BS syringe for Inj. "MOCHIDA"and "F"), we conducted a drug use results survey of this product for its indications, including mobilization of hematopoietic stem cells into peripheral blood and chemotherapy-induced neutropenia. Of the 518 cases enrolled between August 2013 and July 2015, 495 were selected to be subjects of our safety and efficacy evaluations. 37 cases (7.47%)experienced side effects, which were mainly lower back pain(19, 3.84%), fever(8, 1.62%)and bone pain(3, 0.61%). As for serious side effects, interstitial pneumonia was reported in 2 cases, but this disorder has already been ecognized as being associated with the use of filgrastim originator, and there were no reports of unknown side effects calling for immediate attention. In addition, we investigated hypersensitivity reactions(such as nettle rash and anaphylactic shock)and diminished drug effects, both of which are considered to be attributable to immunogenicity, and found that non-serious nettle rash was reported in 2 cases. However, there have been no reports of anaphylactic shock or diminished drug effects. The efficacy rate based on physicians' clinical observations was 97.98%. This study confirmed that there are no problems with the clinical use of filgrastim biosimilar 1.

Neural stem cells (NSCs) in the adult mammalian brain produce new neurons throughout life. Defects in adult neurogenesis can influence neurodegenerative and psychiatric disorders. Hence, understanding long-term maintenance of adult NSCs is crucial. Cell-intrinsic and -extrinsic factors contribute to long-term maintenance of adult NSCs, and we have previously reported that NSCs produce their own niches that send a feedback signal for their own maintenance. In addition, we have identified a slowly dividing subpopulation of embryonic neural progenitor cells that is set aside during development, and later becomes a substantial fraction of NSCs in the adult subventricular zone. Here, we review the mechanisms of long-term maintenance and embryonic origin of adult NSCs. We also discuss current topics on adult NSCs and future perspectives in this field of study.

Repeated cell divisions induce DNA damage accumulation, which impairs stem cell function during aging. However, the general molecular mechanisms by which this occurs remain unclear. Herein, we show that the expression of protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during aging. We observed that HSCs express high levels of Pot1a during development, and this expression declines with aging. Knockdown of Pot1a induced an age-related phenotype, characterized by increased telomeric DDR and reduced long-term reconstitution activity. In contrast, treatment with exogenous Pot1a protein prevented telomeric DDR, which decreased stem cell activity and partially rejuvenated HSC activity. These results highlight a general, reversible mechanism by which aging compromises mammalian stem cell activity, with widespread implications for regenerative medicine.

Cells have developed ingenious defense mechanisms in response to oxidative stress. Here, we evaluated changes in anti-oxidative capacity during differentiation of 3T3-L1 preadipocytes into adipocytes. When 3T3-L1 preadipocytes were treated with H2O2 (0.10-2.0 mM) for 21 h, cell viability decreased in response to H2O2 concentration, with an LD50 of approximately 0.35 mM H2O2. In the cells undergoing differentiation at 2 and 6 d, LD50 increased to 1.0 and >2.0 mM H2O2, respectively. These results indicate that resistance to oxidative stress dramatically increased with progression of differentiation of preadipocytes into adipocytes. Catalase activity and GSH content increased in the differentiated cells at 6 d, whereas superoxide dismutase and glutathione peroxidase activities were slightly lower in adipocytes than in preadipocytes. Moreover, knockdown of catalase or depletion of intracellular GSH enhanced the sensitivity to H2O2. When GSH was added to the cells depleted of intracellular GSH, the antioxidant capacity recovered. Autophagy was increased in differentiated adipocytes but was not affected by H2O2 treatment. Therefore, these results suggest that the increase in intracellular catalase activity and GSH content played a role in the increased anti-oxidative capacity of differentiated 3T3-L1 adipocytes.

We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined.

Ovarian failure-associated infertility is a serious late complication for female patients who have undergone allogeneic hematopoietic stem cell transplantation (SCT). Although the role of a pretransplant conditioning regimen has been well appreciated, the increasing application of reduced-intensity conditioning has led us to reconsider other factors possibly affecting ovarian function after allogeneic SCT. We recently reported that graft-versus-host disease (GVHD) targets granulosa cells of the ovarian follicles, thereby significantly reducing ovarian reserves and fertility after SCT. We also found that ovarian GVHD impairs fertility independently of the toxicities of the conditioning regimens, and pharmacological GVHD prophylaxis preserves fertility after SCT. For the first time, these results demonstrated that GVHD targets the ovary and impairs ovarian functions and fertility, thereby having important clinical implications in young female transplant recipients with nonmalignant diseases, for whom minimally toxic regimens are used. Here we review recently published articles regarding clinical and basic researches on female infertility after SCT.

Mononuclear phagocytes, such as monocytes and dendritic cells (DCs), are essential for tissue homeostasis and immunity. In adults, these cells develop from hematopoietic stem cells via a common progenitor population. We have been investigating the mechanism underlying the development of mononuclear phagocytes from the viewpoint of gene expression control by transcription factors. Particularly, IRF8, the loss of which causes immunodeficiency and chronic myeloid leukemia-like neutrophilia in mice and humans, promotes the development of monocytes and DCs, while it limits neutrophil differentiation. IRF8 cooperates with the myeloid master transcription factor, PU.1, in mononuclear phagocyte progenitors. KLF4 and BATF3 serve as critical transcription factors downstream of IRF8 to induce the differentiation of monocytes and DCs, respectively. Conversely, IRF8 blocks the activity of the transcription factor C/EBPα to suppress the neutrophil differentiation program. Indeed, Irf8-/- mononuclear phagocyte progenitors do not efficiently generate monocytes and DCs and, instead, aberrantly give rise to a large number of neutrophils. Our recent data have begun to uncover the vital role of IRF8 in the establishment of distal enhancers in mononuclear phagocyte progenitors. These results place IRF8 as a central regulator of the development of monocytes and DCs.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell diseases characterized by inefficient hematopoiesis and poor prognosis. There are currently no useful tools for identifying new therapeutic targets of MDS mainly because of a lack of good disease models. Although massive parallel sequencing studies have revealed several MDS-specific genomic alterations that are different from those of de novo acute myeloid leukemia (AML), the relationships between the genetic architecture and pathophysiology in MDS remain poorly understood. We successfully generated multiple iPS cell lines (MDS-iPSC lines) from several patients with either MDS or secondary AML that progressed from MDS. We assessed the hematopoietic differentiation potential of the established MDS-iPSC lines and identified stage-specific maturation defects with graded severity. The MDS-iPSC lines could be a useful tool for elucidating the subclonal diversity, pathogenesis, and clonal evolution of MDS as well as for identifying new therapeutic compounds.

HLA-Flow is a flow cytometry-based method using anti-HLA antibodies against mismatched HLA alleles combined with the antibodies against antigens expressed on leukemic cells. It is a sensitive assay to determine minimal residual disease (MRD) after HLA mismatched hematopoietic stem cell transplantation (HSCT). In this study, we report the results of our HLA-Flow using six-color based multicolor fluorescence-activated cell sorting for HLA-mismatched HSCT. We performed HLA-Flow monitoring after HLA mismatched HSCT from July 2013 to July 2016 in nine patients (three with acute lymphoblastic leukemia, five with acute myeloid leukemia, and one with therapy-related acute myeloid leukemia) for MRD monitoring. We detected a relapse after HSCT in three of the nine patients, two of them at MRD levels. HLA-Flow is a sensitive, fast, and inexpensive method for the detection of MRD in patients with HLA-mismatched HSCT.

Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports.

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1), and its prognosis remains poor. Three to five percent of HTLV-1 carriers, infected mainly by breast feeding, develop ATL after a latency period as long as 70 years. The standard of care for aggressive ATL and indolent ATL comprises intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation, if applicable, and watchful waiting, respectively. Outside Japan, a combination of interferon-α and zidovudine has also been used as a therapeutic option for acute, chronic, and smoldering-type ATLs. A Japanese nationwide retrospective study revealed the outcome of patients diagnosed between 2000 and 2009. The median survival times were 8.3, 10.6, 31.5, and 55.0 months and the 4-year overall survival rates were 11%, 16%, 36%, and 52% for acute, lymphoma, chronic, and smoldering-type ATLs, respectively. Recently, the development of several novel agents has been attempted by targeting surface antigens on ATL cells such as CCR4 and CD30 with monoclonal antibodies, targeting molecular abnormalities in ATL cells with EZH1/2 inhibitor, and modulating the immune environment via immunomodulatory drugs (IMiDs) or immune checkpoint inhibitors. Among them, a CCR4 monoclonal antibody mogamulizumab, and an IMiD, lenalidomide, have been introduced for clinical use in Japan.

Epigenetic regulation holds a key role in gene expression due to its modulation of the structure and function of chromatin. Notably, epigenetic dysregulation is deeply involved in the pathogenesis of hematological malignancies. Polycomb group (PcG) genes encoding histone modifier proteins are representative epigenetic genes that regulate a variety of cellular functions, including self-renewal and multi-lineage differentiation of stem cells. Surprisingly, many PcG genes are targeted by deletions or somatic mutations or both in a number of hematological malignancies, such as myelodysplastic syndrome (MDS). PcG proteins form multiprotein complexes and exert either oncogenic or tumor-suppressive functions, depending on the tumor type. In MDS, they function as tumor suppressors. This review summarizes the current knowledge on deregulated polycomb function in the pathogenesis of MDS.