The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34CD38IL-3RαCD45RA common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41 CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis.

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Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.

Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.