To identify HLA alleles closely involved in the autoantigen presentation in acquired aplastic anemia (AA), we studied the HLA allelic loss frequencies of 312 AA patients, including 43 patients with loss of heterozygosity of 6p chromosome (6pLOH). An analysis of the HLA alleles contained in the lost haplotype revealed to be the most frequently lost allele. When we examined 28 AA (12 6pLOH[+] and 16 6pLOH[-]) patients with for the presence of leukocytes lacking HLA-B4002 (B4002) using a new monoclonal antibody specific to this allele, B4002 granulocytes were detected not only in all 6pLOH(+) patients but also in 9 (56%) of the 16 6pLOH(-) patients. Furthermore, 10 (83%) of the 12 6pLOH(+) patients possessed 1.0% to 78% B4002 granulocytes that retained the HLA-A allele on the same haplotype (B4002A), suggesting the frequent coexistence of granulocytes that underwent mutations restricted to with 6pLOH(+) (B4002A) granulocytes. Deep sequencing of the of sorted B4002A granulocytes revealed various somatic mutations, such as frameshift, nonsense, and splice site mutations, in all 15 patients studied. Surprisingly, missense mutations in the α-3 domain of that are not involved in the antigen presentation were detected exclusively in the B4002 granulocytes of 3 patients possessing B4002 granulocytes. The markedly high prevalence of leukocytes lacking HLA-B4002 as a result of either 6pLOH or structural gene mutations, or both, suggests that antigen presentation by hematopoietic stem/progenitor cells to cytotoxic T cells via the HLA-B allele plays a critical role in the pathogenesis of AA.

Key Points• HLA-lacking iPSCderived HSCs from aplastic anemia patients show a hematopoietic ability similar to wild-type iPSC-HSCs.• iPSC-HSCs that lack HLA-B4002 escape specific T-cell attack.Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number

Dysregulation of T-cell–mediated immunity is responsible for acquired pure red cell aplasia (PRCA). Although STAT3 mutations are frequently detected in patients with T-cell large granular lymphocytic leukemia (T-LGLL), which is often complicated by PRCA and which is also reported to be associated with acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS), whether STAT3-mutated T cells are involved in the pathophysiology of PRCA and other types of bone marrow failure remains unknown. We performed STAT3 mutation analyses of the peripheral blood mononuclear cells from PRCA patients (n = 42), AA (n = 54), AA–paroxysmal nocturnal hemoglobinuria (AA-PNH; n = 7), and MDS (n = 21) using an allele-specific polymerase chain reaction and amplicon sequencing. STAT3 mutations were not detected in any of the 82 patients with AA/PNH/MDS but were detected in 43% of the 42 PRCA patients. In all 7 STAT3-mutation–positive patients who were studied, the STAT3 mutations were restricted to sorted CD8+ T cells. The prevalence of STAT3 mutation in idiopathic, thymoma-associated, autoimmune disorder–associated, and T-LGLL–associated PRCA was 33% (5 of 15), 29% (2 of 7), 20% (1 of 5), and 77% (10 of 13), respectively. The STAT3-mutation–positive patients were younger (median age, 63 vs 73 years; P= .026) and less responsive to cyclosporine (46% [6 of 13] vs 100% [8 of 8]; P= .0092) in comparison with STAT3-mutation–negative patients. The data suggest that STAT3-mutated CD8+ T cells may be closely involved in the selective inhibition of erythroid progenitors in PRCA patients.

Key Points HSPCs that lack HLA class I alleles can sustain clonal hematopoiesis without driver mutations or telomere attrition in AA patients. 6pLOH may confer a survival advantage to HSPCs with age-related somatic mutations, leading to the clonal expansion of mutant HSPCs.

BK virus-associated hemorrhagic cystitis (BKV-HC) is a common and major cause of morbidity in recipients of allogeneic hematopoietic stem cell transplantation. A 32-year-old woman developed severe BKV-HC on day 24 after cord blood transplantation (CBT). Despite supportive therapies - such as hyperhydration, forced diuresis, and urinary catheterization - macroscopic hematuria and bladder irritation persisted for over a month. Hyperbaric oxygen (HBO) therapy at 2.1 atmospheres for 90 min per day was started on day 64 after CBT. Macroscopic hematuria resolved within a week, and microscopic hematuria was no longer detectable within 2 weeks. Hematuria did not recur after 11 sessions of HBO therapy, and no significant side effects were observed during or after treatment. HBO therapy could thus be useful in controlling refractory BKV-HC after CBT.