Classic hairy cell leukemia (classic HCL) is a rare disease associated with indolent mature B-cell lymphoma. A 50-year-old man presented with pancytopenia for 3 years and was diagnosed with classic HCL because his lymphoid cells showed a hairy morphology with oval nuclei and indistinct nucleoli both in the peripheral blood and bone marrow (BM) smears. Flow cytometric analysis revealed that these cells expressed CD11c, CD25, and CD103, and the Sanger sequence method detected BRAF V600E mutation. Cladribine (0.09 mg/kg/day) was initiated for 7 days via continuous intravenous injection. On day 13, the patient died from bloodstream infection caused by methicillin-resistant Staphylococcus epidermidis. Autopsy findings revealed BM necrosis without residual leukemia cells caused by classic HCL, severe infection, and agents, such as cladribine and granulocyte-colony stimulating factor; however, its cause remained undetermined. Both early diagnosis and immediate clinical intervention are required to improve the clinical outcomes in classic HCL. The cause of hematopoiesis disturbance should also be identified using BM biopsy or magnetic resonance imaging before initiating treatment in classic HCL with severe pancytopenia.

Sweet syndrome is a rare inflammatory disease with rapid onset of painful, edematous skin eruptions, and neutrophilia. Concerning hematological disorders, Sweet syndrome often presents in patients with myeloid diseases, but it is rarely observed in patients with lymphoid diseases. Here we describe a 72-year-old male with Philadelphia chromosome-positive acute lymphoblastic leukemia who suffered recurring Sweet syndrome. Following induction chemotherapy, granulocyte colony-stimulating factors (G-CSFs) were administered due to febrile neutropenia. A few weeks thereafter, skin eruption emerged on the palmar and dorsal surfaces of his hands, and skin biopsy confirmed Sweet syndrome. His symptoms improved with the short-term use of prednisolone. After recovering from the neutropenia, the patient received percutaneous coronary intervention (PCI) due to unstable angina that developed after the induction chemotherapy. During PCI, coronary artery dissection caused cardiopulmonary arrest. The patient recovered with intensive care. However, blood tests on the following day revealed marked neutrophilia. The skin eruption re-emerged on both hands, which was consistent with Sweet syndrome. Sweet syndrome repeatedly occurred after the recovery of neutropenia due to chemotherapy. We suggest that the intrinsic increase in G-CSF in response to inflammation might have caused recurring Sweet syndrome in this patient.

Primary adrenal lymphoma is a rare lymphoma, accounting for <0.2% of non-Hodgkin lymphoma. The leading histopathological subtype of adrenal lymphoma is diffuse large B-cell lymphoma, and intravascular large B-cell lymphoma (IVLBCL) is rare. Here, we report a case of IVLBCL occurrence as a bilateral adrenal gland tumor, which was diagnosed by CT-guided biopsy. Tumor cells were positive for CD20 and MUM-1 but not for CD10 on immunostaining, suggesting non-germinal center B-cell subtype lymphoma. In addition, the triple expression of BCL2, BCL6, and MYC was demonstrated on tumor cells. The bone marrow examination revealed the involvement of lymphoma cells but not hemophagocytosis. The chromosomal analysis revealed complex karyotypic abnormalities without a rearrangement of BCL2 or MYC using FISH analysis. Although the patient responded to R-CHOP chemotherapy, he developed central nervous system involvement by lymphoma. To date, the significance of the triple expression of BCL2, BCL6, and MYC without gene translocation remains partially elucidated. Therefore, an accumulation of similar cases is needed to elucidate the pathogenesis and clinical significance of the triple expression of these oncoproteins.

Cardiac involvement during lymphoma often causes complications, including arrhythmia. A 68-year-old male with cardiac tamponade was diagnosed with diffuse large B-cell lymphoma with cardiac involvement based on the presence of the tumor mass in the myocardium and lymphoma cells in the pericardial effusion. He developed atrial fibrillation, ventricular tachycardia, and atrial flutter after initiating chemotherapy. Following chemotherapy, sinus rhythm was restored without invasive treatment for arrhythmia, while the cardiac mass disappeared. No recurrent arrhythmias were observed. In lymphoma with cardiac involvement, unexpected arrhythmias can emerge after initiation of chemotherapy, which could potentially be related to accelerated cardiac remodeling owing to the rapid relief of cardiac damage. Follow-up using electrocardiogram is thus necessary during chemotherapy for cardiac lymphoma, despite the absence of arrhythmia at the time of diagnosis.

Genetic abnormalities of acute myeloid leukemia (AML) include chromosomal translocations and gene mutations. Commonly observed chromosomal abnormalities in AML are t (8;21), t (15;17), inv (16), and 11q23-related translocations. These aberrations produce RUNX1-RUNX1T1, PML-RARA, CBF-MYH11, and MLL-fusion genes, respectively, which promote leukemic stem cell formation by interfering with hematopoietic differentiation and enhancing the self-renewal capacity of hematopoietic cells. Gene mutations recurrently occur in transcription factors, signaling molecules, tumor suppressor genes, epigenetic regulators, RNA splicing factors, and cohesion complexes, with FLT3, NPM1, and DNMT3A being the most frequently mutated genes in AML. Recent studies disclosed the biological function of mutated genes and their correlation with prognosis. Based on these findings, development of novel therapeutic drugs targeting mutated genes or dysregulated genetic pathways is underway.

Standard treatment for acute myeloid leukemia (AML) comprises (1) induction therapy with both cytarabine and anthracycline and (2) consolidation therapy that is modified according to patients' conditions, including prognostic factors. However, this strategy is not satisfactory, especially for elderly patients. Novel technologies have revealed several driver mutations of numerous critical genes in AML, which can be targeted by novel drugs; the discovery of such targetable genes and the development of novel drugs have evolved the treatment strategy for AML. We should always monitor these advances in hematology. In the United States, the FDA has already approved several new drugs for AML, including FLT3 inhibitors and IDH neoenzyme inhibitors. In Japan, gilteritinib, an FLT3 inhibitor, was also approved at the end of 2018. These promising drugs will facilitate performing “precision medicine” on patients with AML soon.

Myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are heterogeneous myeloid neoplasms that frequently evolve into secondary acute myeloid leukemia (sAML). Recent progress in next-generation sequencing technologies has allowed us to discover frequent mutations throughout the coding regions of MDS, MDS/MPN, and sAML, subsequently providing information on more than 60 driver genes in these diseases. As shown by many study groups recently, such driver mutations are acquired in a gene-specific fashion. DDX41 and SAMD9/SAMD9L mutations are observed in germline cells long before MDS presentation. In blood samples from healthy elderly individuals, somatic DNMT3A, TET2, and ASXL1 mutations are detected as age-related clonal hematopoiesis and supposed to be a risk factor for hematological neoplasms. Recent reports on MDS have shown that mutations in genes such as NRAS and FLT3, designated as Type I genes, were significantly associated with leukemic evolution. Another type (Type II) of genes, including RUNX1 and GATA2, has been shown to be related to the progression from low-risk to high-risk MDS. These driver mutations are significantly concomitant during disease progression. Overall, various types of driver mutations are sequentially acquired in MDS, accounting for the heterogeneity of these disorders.

Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, characterized by constitutive activation of JAK/STAT signaling. JAK2, MPL, and CALR mutations are considered “driver mutations” and are directly implicated in the disease pathogenesis by activation of JAK2/STAT signaling. In addition to these driver mutations, several other mutations in epigenome regulatory and RNA splicing molecules have been found. This genetic information, especially regarding driver mutations, is essential for the diagnosis of MPN. Furthermore, assessment of non-driver mutations is also becoming increasingly important for disease risk assessment and treatment strategy definition.

Since the introduction of hematopoietic stem cell transplantation (HSCT), matching the HLA with the donor and recipient is the most important factor in improving the outcome. Currently, we are getting familiar with cord blood transplantation and haplo-identical stem cell transplantation which are beyond HLA disparity. However, even in this era, the significance of HLA for HSCT has not changed, and new technology provides knowledge regarding HLA and HSCT. Usually, HLA typing methods only estimate the allele, but next generation sequencing (NGS) can detect the whole sequence of the HLA gene. Moreover, because the NGS method can be used for quantitative analysis, we can also detect 6pLOH in some disease conditions. Furthermore, a previous report showed that HLA epitope mismatch also influenced the outcome of HSCT. This review shows this new technology and findings on HLA and HSCT.

Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment for patients with hematological malignancies with donor selection being one of the most important decisions for its success. Several possible donor options have been available, including matched related donor (MRD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), umbilical cord blood (UCB), and HLA-haploidentical donor. A MRD remains the preferred donor option for optimal transplant outcomes with approximately 30% of the patients having such a donor. Therefore, the remaining 70% of patients require an alternative donor source. Although a MUD is considered to be the next preferred donor option following a MRD, searching for a MUD may delay transplantation for patients unlikely to have a MUD. UCB or HLA-haploidentical donors allow for shorter time to transplant but are associated with increased risk. Recently, T-cell-replete haploidentical transplantation using posttransplantation cyclophosphamide (PTCY) has been developed. This strategy dramatically reduces the risk of graft versus host disease (GVHD), while transplant outcomes after PTCY-based HLA-haploidentical stem cell transplantation seem to be equivalent to those after HLA-matched stem cell transplantation. Recent advances in GVHD prophylaxis may change the algorithm for donor selection.

In patients who undergo hematopoietic stem cell transplantation (HSCT), cytomegalovirus (CMV) infection directly or indirectly increases all-cause and non-relapse mortality rates. Although preemptive therapy suppresses CMV infection, it does not improve non-relapse mortality rates in patients with CMV reactivation compared to patients with no CMV reactivation. According to the World Health Organization International Standards (WHO IS), quantitative polymerase chain reaction has been recently adopted as the global standard for monitoring CMV, and maribavir, brincidofovir, and letermovir have been developed as new antiviral drugs for the treatment of CMV infection. Letermovir, a first-class anti-CMV agent, strongly inhibits the CMV DNA terminase complex, which is required for viral DNA cleavage and packaging. It significantly suppressed CMV infection in a phase III clinical trial, thereby improving the overall survival of patients who undergo HSCT. Vaccines and cell therapies for CMV must be further developed.

Hemophilia is the most common congenital coagulation disorder, characterized by a tendency to bleed severely. Treatment is based on the replacement of defective FVIII or FIX. Following the introduction of recombinant FVIII and FIX, the treatment paradigm of the disease is shifting from episodic to prophylactic treatment with regular the infusion of factor concentrates. Since 2000, several new recombinant FVIII and FIX products with longer half-life have been developed by pegylation protein modification and other technologies, resulting in improved quality of life for patients with hemophilia. Recently, therapeutics with novel hemostatic mechanisms have been developed to overcome several unmet needs. FVIII (a), mimicking bispecific antibody recognizing FIX (a) /FX, has been approved in Japan. The product has several advantages, including a much longer half-life spanning 30 days, subcutaneous injectability, and effectiveness irrespective of the presence of FVIII inhibitor. The paradigm of hemophilia treatment is now shifting towards intact joint function and higher activity.

Disseminated intravascular coagulation (DIC) is a serious disease that, in the presence of underlying disease, causes persistent, generalized, marked coagulation activation and recurrent formation of microthrombi in microvessels. Although the DIC pathophysiology differs from that of thrombotic microangiopathy (TMA), distinguishing the two is sometimes challenging. At least, differential diagnosis using coagulation tests of values such as PT and APTT is difficult. While the mechanisms of DIC development differ according to the underlying disease, tissue factor plays a vital role in common. The classification of the DIC type is essential not only for understanding pathophysiology but also for the appropriate choice of DIC treatment. As a revision of the old DIC diagnostic criteria of the Japanese Ministry of Health, Labour and Welfare, new diagnostic criteria for DIC have been established by the Japanese Society on Thrombosis and Hemostasis (2017 edition). The new criteria are estimated to play a pivotal role in the future diagnosis of DIC. From the perspective of analysis by genetic techniques, the protein C/thrombomodulin system and plasminogen activator inhibitor play crucial roles in the control and development of DIC.

Recently, in Japan, the number of patients with autoimmune acquired coagulation factor deficiency (AiCFD) due to anti-coagulation factor autoantibodies has been on the rise. There are several types of such autoantibodies, which can be generated against any coagulation factor: 1) the neutralizing type binds the functional region (s) of a coagulation factor to inhibit its activity (inhibitor type) ; 2) the non-neutralizing type binds the nonfunctional region (s) of a coagulation factor and enhances its clearance from circulation (hyperclearance type) ; 3) the combination of types 1) and 2). Despite clinical manifestations of AiCFD ranging from asymptomatic laboratory abnormalities to fatal exsanguination or even to thromboembolic events, most patients with AiCFD exhibit certain bleeding symptoms. Owing to the major bleeding symptoms of AiCFD not being specific for any particular disease, laboratory tests are essential for the early diagnosis of AiCFD, selection of proper treatment, and assessment of a therapy's efficacy. Because of severe ongoing hemorrhages and anemia, most patients are administered large amounts of the deficient coagulation factors. Moreover, given the rarity of this disease, there is no standardized therapeutic modality for antibody eradication. Most patients receive corticosteroids as first-line immunosuppressive medicines; however, some patients become treatment-resistant or develop a recurrence despite achieving remission once.

Recent progress in whole genome sequencing has identified recurrent somatic mutations in the additional sex combs like 1 (ASXL1) gene in a variety of hematological disorders and even in premalignant conditions. However, the molecular mechanisms regarding the contribution of ASXL1 mutation to the pathogenesis of premalignant conditions remain largely unelucidated. Thus, we investigated the biological effects of mutant Asxl1 using newly-generated knock-in (KI) mice. Heterozygous mutant KI mice developed phenotypes resembling human low-risk myelodysplastic syndromes (MDS), and some of them developed an MDS/myeloproliferative neoplasm-like disease after a long latency. The H2AK119ub1 level around the promoter region of p16^Ink4a was significantly decreased in KI hematopoietic stem cells (HSCs), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutant Asxl1. The mutant Asxl1 failed to interact with Bmi1, although wild type ASXL1 protein did not. When p16^Ink4a expression was depleted in Asxl1 KI mice, the HSC pool was restored, and apoptosis was ameliorated in HSCs. These findings demonstrate that the loss of protein interaction between mutant Asxl1 and Bmi1 affected the activity of Prc1. The subsequent derepression of p16^Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in heterozygous Asxl1 KI mice.

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies, resulting from mutations in one of the 22 known FANC genes (from FANCA to FANCW). The proteins encoded by these genes participate in a deoxyribonucleic acid interstrand cross-link repair pathway, the so-called FA/BRCA pathway. The 22 FANC genes include hereditary breast and ovarian cancer susceptibility genes, such as BRCA1 or BRCA2. Patients with FA display a wide range of clinical phenotypes owing to the genetic heterogeneity of the disease; therefore, the molecular diagnosis is critical for the appropriate management of such patients. Recently, we successfully subtyped 97% of the 117 Japanese patients with FA and identified 215 mutant alleles through a comprehensive strategy. In this review, the characteristics of genetic subtyping and mutated FANC gene variants in Japanese patients with FA and the genotype-phenotype correlation in FA are summarized. In addition, the carrier frequency of pathogenic FANC genes and risk of cancer among the FANC gene mutation carriers in general Japanese population are discussed.

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes associated with DNA repair and telomere maintenance. In addition, mutations in ribosome-related genes cause defective hematopoiesis. Patients with IBMFS exhibit a predisposition to developing hematological malignancy or solid tumor because of the defect in cellular and molecular hemostasis. The SAMD9 mutation causes the multisystem disorder, MIRAGE syndrome, characterized by congenital adrenal hypoplasia and loss of chromosome 7, providing a novel insight into the correlation between the germline and somatic mutations of SAMD9/SAMD9L and myelodysplastic syndrome (MDS) with monosomy 7. Primary immunodeficiency diseases (PID) are caused by inborn errors of the immune system. PID patients with inadequate tumor immunity are at an elevated risk of developing malignancies such as lymphoma, leukemia, and gastrointestinal cancer. Recently, monocytopenia and mycobacterial infection (MonoMAC) syndrome with the GATA2 gene mutation have been reported as PID related to bone marrow failure. Patients with MonoMAC syndrome often develop MDS and acute myeloid leukemia. Here, we present the pediatric-onset IBMFS and/or PID with cancer predisposition and briefly discuss the tumorigenesis in each monogenic disease.

Lymphoproliferative disorders (LPDs) are caused by dysregulated lymphocyte proliferation and include polyclonal benign and monoclonal malignant diseases. LPDs frequently occur in immunocompromized patients, particularly those with primary immunodeficiency disease (PID), a monogenic disease. PID-associated LPD corresponds to inherited LPD. Here, we describe inherited LPD and focus on IKZF1-associated diseases and Epstein-Barr virus-associated LPD, such as ZAP70 deficiency and X-linked lymphoproliferative syndrome type 1 with somatic reversion mosaicism. Disclosing the pathogenesis of inherited LPDs would lead to a broad understanding of LPDs and development of new treatment strategies.

Recent remarkable advancements in cancer immunotherapy have rendered adoptive T cell therapy an option of clinical treatment of patients with cancer following the success of immune checkpoint inhibitors. In 2017, the FDA approved adoptive cell therapy with chimeric antigen receptor (CAR) gene-modified T cells as a treatment for patients with acute lymphocytic leukemia and diffuse large cell lymphoma. In February this year, it was announced that this therapy will also be approved in Japan soon. Adoptive therapy with T-cell receptor (TCR) gene-modified T cells is a promising therapy for patients with hematological malignancy and solid tumors that follow the success of CAR-T cell therapy. This review aims to summarize the recent progress and issues of TCR gene-modified T-cell therapy with the introduction of our recent study.