Somatic mutations in the ASXL1 gene are commonly observed in myeloid neoplasms. Pathogenic ASXL1 mutations induce the expression of C-terminally truncated mutant ASXL1 protein. We have shown that wild-type ASXL1 is a phase-separating protein involved in the formation of paraspeckles, one of the best known membraneless organelles (MLOs). Mutant ASXL1 lacks the intrinsically disordered region, which is important for phase separation and fails to support paraspeckle formation. Additionally, paraspeckles are disrupted in hematopoietic cells derived from ASXL1-MT knockin mice. The disruption of paraspeckles in hematopoietic cells results in a dysfunction of the hematopoietic reconstitution capacity. Therefore, this review presents our findings and summarizes the knowledge of phase separation and MLOs as a hot topic in cell biology.

A 28-year-old female was diagnosed with acute myeloid leukemia (AML) due to t (8;21) (q22;q22.1); RUNX1-RUNX1T1 at 21 weeks of gestation. Because no adverse prognostic genetic mutations were discovered, we decided to continue the pregnancy without chemotherapy for as long as possible. After careful monitoring with blood tests every two weeks, the disease did not progress until full-term, and a cesarean section was performed at 39 weeks of gestation. About two months after delivery, blasts in the peripheral blood increased to 46.5%, and myeloblasts in the bone marrow increased to 21.2%. The patient received idarubicin and cytarabine induction therapy, followed by three cycles of high-dose cytarabine consolidation therapy, and complete remission was maintained. Here we report a rare case who could avoid chemotherapy until full-term labor without progression of AML.

A 71-year-old woman complained of nausea and anorexia. Laboratory tests revealed significant neutrophilia and immunoglobulin A-kappa type M proteinemia, as well as increased plasma cells on bone marrow examination. Furthermore, the serum granulocyte-colony stimulating factor (G-CSF) concentration was high at 160 pg/ml, and the colony stimulating factor 3 receptor (CSF3R)-T618I mutation was negative. Immunohistochemical (IHC) analysis of bone marrow specimens using the anti-G-CSF antibody revealed immunopositivity of some myeloma cells. The patient was diagnosed using G-CSF-producing myeloma and was treated with daratumumab, lenalidomide, and dexamethasone. Her treatment resulted in a very good partial response, with normalization of both serum G-CSF levels and neutrophil count. There have been a few cases of G-CSF -producing myeloma reported, and it has previously been reported as chronic neutrophilic leukemia with M proteinemia. According to previous reports, techniques such as serum G-CSF measurements, IHC with an anti-G-CSF antibody, and CSF3R gene mutation analysis are useful for differentiating G-CSF-producing myeloma. However, the clinical characteristics and long-term prognosis of G-CSF-producing myeloma remain unknown. Additional case gathering and investigations are required.

Immunosuppressive therapy (IST) is the first-line treatment for patients with aplastic anemia (AA) who require blood transfusion when a human leukocyte antigen-matched related donor is unavailable. However, the proportion of patients with AA who are refractory to IST remains high (30%). IST in combination with eltrombopag has been studied in adults, but its efficacy and safety in children have not been established. We present three cases of AA that were initially refractory to IST but improved with additional eltrombopag administration. These patients were successfully managed using this strategy without the use of hematopoietic cell transplantation (HCT). The first patient achieved a complete response within one month after receiving eltrombopag. When the second and third patients were given eltrombopag, they were able to safely reduce the amount of cyclosporin they were given. They avoided blood transfusions, but no measurable response was obtained. The conjunctival icterus was detected and treated using a dose reduction of eltrombopag. Eltrombopag may be effective in children with AA who are refractory to IST, allowing them to avoid blood transfusions and HCT. More cases treated with this strategy are needed to confirm its efficacy and safety for children with AA.

A 72-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) was treated with dasatinib (week1: 50 mg/day, week2: 70 mg/day, week3-: 100 mg/day) and prednisolone from June 2017. However, in January 2018, it relapsed with the T315I mutation. Although the treatment was changed to ponatinib 30 mg/day, he experienced a second relapse in June 2018. Following confirmation of CD22 positivity, he was treated with three cycles of inotuzumab ozogamicin (InO), resulting in CR. He was CR for 2.9 years before relapsing for the third time in May 2021. Because the patient was still CD22-positive, InO was given again, and the patient achieved CR at the end of the second cycle. We had a case where re-administering InO was effective as a salvage therapy for relapsed/refractory Ph+ALL (r/r Ph+ALL) in an elderly patient.

Myelodysplastic syndromes (MDS) are a clonal disorder based on genomic mutations in hematopoietic stem cells. They are categorized as lower-risk MDS, characterized by peripheral cytopenia; and higher-risk MDS, characterized by progression to acute myeloid leukemia. Previous studies reported that inflammation and immune activation are deeply involved in the pathogenesis of lower-risk MDS. Recent studies elucidated the molecular basis for the activation of inflammatory pathways via dysregulated innate immune system and the resultant cell-death acceleration in lower-risk MDS. Conversely, immunosuppression and immune escape are substantially involved in the pathogenesis and disease progression of higher-risk MDS. VEXAS syndrome is an autoinflammatory disease characterized by clonal hematopoiesis with somatic mutation of UBA1 in hematopoietic stem and progenitor cells and has attracted broad attention as a lower-risk MDS model caused by systemic inflammation. Although therapeutic effects of immunosuppressants are observed for a limited number of patients with lower-risk MDS with inflammation, an optimal treatment should be developed based on their pathology.

Epstein-Barr virus (EBV) has the ability to immortalize not only B cells but also T and natural killer (NK) cells. The virus may also contribute to the onset of EBV-positive lymphoproliferative disorders (EBV-LPDs) by inducing the introduction of gene mutations. It is known that B cell EBV-LPDs (B-EBV-LPDs) develop with preexisting immunodeficiency, but the onset mechanism of T cell and NK cell EBV-LPDs (T-EBV-LPDs and NK-EBV-LPDs), also known as chronic active EBV disease and associated diseases, is unclear. The diagnosis of both EBV-LPDs requires the quantitative examination of EBV-DNA in the peripheral blood. Eliminating the cause of immunodeficiency or administering rituximab is effective in treating B-EBV-LPDs, but some B-EBV-LPDs and T-EBV-LPDs/NK-EBV-LPDs are resistant to pharmacotherapy. Therefore, further research is needed to explicate the pathophysiology of EBV-LPDs and develop a drug for its treatment.

Primary immunodeficiency diseases (PID) are caused by abnormalities in molecules involved in the immune system, and there are nearly 500 genes associated with PID. The symptoms are not only susceptibile to infectious diseases but also to autoimmune diseases, malignancies, autoinflammatory diseases, and allergies. Thus, these diseases are considered inborn errors of immunity (IEI) rather than PID. IEI is typically thought to occur in childhood because IEI is associated with a genetic variant, but there are also several adult-onset IEIs. The same 10 warning signs used to diagnose IEI in children are used to diagnose the condition in adults as well, who are then given a definitive genetic diagnosis after a 4-step diagnostic process. In addition to prophylactic antimicrobial agents and immunoglobulin replacement therapy, allogeneic hematopoietic cell transplantation (HCT) is performed as a curative therapy in some patients with IEI. However, in adult patients with IEI, HCT may have to be stopped due to complications. Adult patients with IEI need to be promptly assessed for HCT, and HCT must be done before complications increase.

Immune checkpoints suppress inappropriate immune responses to self-molecules or cells. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) expressed in T cells are representative molecules involved in the immune checkpoint system. The recent advent of immune checkpoint inhibitors (ICIs) has drastically changed cancer immunotherapy because a substantial proportion of patients with advanced cancers have responded to ICIs and some of them have been cured. This benefit is due to T-cell rescue from immune suppression in their tumor microenvironment by blocking cluster of differentiation 80/CTLA-4 and PD-L1/PD-1 interactions. However, blocking these interactions also liberates T cells that are reactive to self-antigens from tolerance, resulting in the occurrence of autoimmune diseases, that is, immune-related adverse events. Although the primary target organs are the lungs, gastrointestinal tract, and endocrine glands, hematopoietic cells are also affected in 0.5-3% of patients, potentially resulting in anemia or thrombocytopenia. Because hematopoietic system homeostasis is critical to maintaining life support, the occurrence of grade 3-4 irAEs in the hematopoietic system is directly life-threatening. Herein, we review the relationship between ICIs and toxicities in patients with cancer and describe the characteristics and management strategies for hematological immune-related adverse events.

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disease of cytotoxic T cells or NK cells with LGL morphology and frequently complicated cytopenia and/or different autoimmune diseases, which often require medical interventions, although LGL leukemia itself is seldom lethal. Immunologic dysregulations in LGL leukemia contribute to the development of complications, for example, neutropenia with the involvement of Fas ligand system and, in pure red cell aplasia, which is a common complication among the patients of East Asian origin, impairing erythroid developments by cytotoxic T cells. Rheumatoid arthritis (RA) is the most prevalent nonhematological consequence, and Felty syndrome, a rare form of RA, and T-LGL leukemia have a lot in common. When patients have LGL leukemia-associated complications, immunosuppressive medication is a mainstay of treatment. Characteristic mutational features in STAT3, STAT5B, CCL22, and other genes in specific subtypes of LGL leukemia have been detected, that would be associated with immunologically mediated molecular pathogenesis in LGL leukemia, and these new findings may help in creating optimal diagnostic approaches or novel therapies for LGL leukemia.

The Women Doctors Career Symposium entitled “Dreams: Female Hematologists’ Talk” was held at the 84th Annual Meeting of the Japanese Society of Hematology. I would like to share my experience as a board-certified “hematologist” and “clinical laboratory physician.” Certified clinical laboratory physician is one of the 19 fundamental areas in the Japanese Medical Specialty board, but the number is small, and it is also an area where hematologists can easily face challenges. It also allows you to balance career advancement and various life events. It is extremely difficult to forge one’s own path, but it is relatively simple to take the advice of others and choose one’s path. “We cannot direct the wind, but we can adjust the sails.” This is one way to consider continuing a career.

I would like to express my sincere gratitude to be given such an honorable opportunity. I am more than happy to share my personal experience as one example of the diversity of women in hematology. After graduating from Tohoku University, I began my residency training at Japanese Red Cross Musashino Hospital and Tokyo Metropolitan Bokutoh Hospital, which are extremely busy designated hospitals in Tokyo. Both had highly active emergency care centers, and I believe that the rigorous training I received there not only honed my basic patient care skills, but also increased my physical and mental strength. Since I referred many patients to National Cancer Center Hospital, I found it amusing that Dr. Fukuda recruited me based on the recommendation of those patients. I was so fortunate to have many opportunities to contribute as a primary investigator in meaningful nationwide clinical studies. At present, I appreciate my country life as a community hematologist-oncologist. I also did not expect that I would have continuing opportunities to collaborate with researchers nationwide thanks to rapid progress in remote communications, and nothing would make me happier than to continue participating in projects on cancer survivorship.

Recent advances in intensive treatment strategies have resulted in an overall treatment rate of approximately 70% for pediatric cancers. The most notable improvement in clinical outcomes has been observed for acute lymphocytic leukemia, with the cure rate increasing from approximately 10% 50 years ago to 90% at present. However, relapsed and refractory cases of childhood leukemia continue to have a poor prognosis, and there is no standard treatment strategy for many cases. Moreover, even in cases with favorable outcomes, growth retardation and endocrine disorders are major complications. To improve the cure rate of pediatric cancers, we have focused on the molecular mechanisms of leukemia, the most common type of pediatric cancer. In this symposium, recent findings on T-cell acute lymphocytic leukemia will be outlined.