The hematopoietic system performs essential functions for living organisms through a wide array of cell types, including immune cells for host defense, erythrocytes for oxygen transport and megakaryocytes involved in vascular and tissue repair. The adoptive transfer of mature blood cells and the transplantation of hematopoietic stem cells (HSCs) have been extensively exploited in clinical settings, for the treatment of inherited blood disorders as well as blood malignancies. In addition, blood cells are also preferential targets in the context of gene therapy, where they provide revolutionary treatments not only for classical hematologic diseases but also for novel and unexpected indications, such as inherited metabolic disorders. However, clinical bottlenecks remain, including the limited availability of suitably matched donor cells, the need for high cell doses, and the complexity of personalized manufacturing.Given their proliferative ability and capacity to generate any human cell type, human pluripotent stem cells (hPSCs), encompassing both embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent a novel, potentially unlimited, easy-to-engineer source of either patient-specific or allogeneic blood cells for "off-the-shelf" cell therapies. In parallel, hPSC-derived blood cells enable in vitro modeling of diverse hematologic diseases and the identification of novel therapeutic targets. Recent advances describing protocols for the de novo generation of HSCs are opening new and exciting avenues for a broad application of hPSC-derived blood cells in both basic research and clinical medicine.

Most patients with early-stage classical Hodgkin lymphoma (cHL) are treated with doxorubicin, bleomycin, vinblastine, and dacarbazine with or without radiation therapy, although studies are now evaluating the incorporation of novel agents paired with abbreviated chemotherapy. We present the efficacy and safety of brentuximab vedotin (BV) and nivolumab in combination with doxorubicin and dacarbazine (AN+AD) in patients with early-stage cHL. In this phase 2 study, patients with non-bulky (<10 cm) Ann Arbor stage I or II cHL received 4 cycles of AN+AD. The primary endpoint was complete response (CR) rate at end of treatment (EOT) by investigator. At the time of this analysis, 154 patients received ≥1 dose of AN+AD. The objective response rate at EOT was 96% (95% CI, 91.7-98.6), and the CR rate was 92% (95% CI, 86.0-95.4). In the favorable (n=56) and unfavorable (n=97) subgroups, CR rates were 95% (95% CI, 85.1-98.9) and 91% (95% CI, 83.1-95.7), respectively. The proportion of patients with duration of CR of at least 2 years was 96% (95% CI, 90.9-98.4). At a median follow-up of 27.9 months, the estimated 2-year PFS rate was 97% (95% CI, 92.0-98.8). Any-grade and grade ≥3 treatment-emergent adverse events occurred in 99% and 44% of patients, respectively; no events of febrile neutropenia were reported. Any-grade treatment-emergent immune-mediated adverse events occurred in 22% of patients. One disease-related death was reported after the safety reporting period. Results from this study support the use of BV and nivolumab in combination with limited chemotherapy in patients with non-bulky, early-stage cHL. ClinicalTrials.gov: NCT03646123.

Intestinal Enterococcus domination has been associated with an increased risk of mortality from acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), a curative-intent treatment for patients with hematologic malignancies. In this study, we investigated interactions between Enterococcus and the intestinal epithelium as a mechanism to aggravate GVHD. We observed that endogenous intestinal Enterococcus outgrowth was associated with increased GVHD mortality and major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells in the colon in an MHC-disparate mouse model of GVHD. Monocolonization of nontransplanted gnotobiotic mice with Enterococcus faecalis was sufficient to induce colonic MHC-II expression. Conversely, select species within the genus Enterococcus, as well as a consortium of 4 anaerobic commensal bacteria including Blautia producta, did not affect colonic MHC-II expression in gnotobiotic mice. In addition, E faecalis colonization induced inflammatory responses in CD4+ T cells and natural killer cells from the colonic lamina propria, the 2 main sources of interferon gamma production that drives MHC-II expression in nonprofessional antigen-presenting cells. We further explored the potential therapeutic benefit of establishing colonization resistance against E faecalis through administration of a lantibiotic-producing B producta strain after allo-HCT. Colonization of transplanted mice with a consortium of commensal bacteria containing the lantibiotic-producing B producta strain prevented intestinal Enterococcus domination after transplantation and improved GVHD survival. Our results demonstrate a potential mechanism by which Enterococcus aggravates GVHD through increased MHC-II expression in the intestinal epithelium. Targeting the Enterococcus-epithelium-MHC-II axis thus presents a therapeutic opportunity to prevent lethal GVHD.

NUTM1 rearrangement defines a significant subset of B-cell acute lymphoblastic leukemia (B-ALL), particularly in infants lacking KMT2A rearrangements, yet its underlying molecular characteristics remain poorly understood. Here, we establish that NUTM1-rearranged (NUTM1-r) leukemia is a discrete entity characterized by a unique transcriptional and epigenetic landscape, notably featuring global DNA hypomethylation, irrespective of the 5' fusion partner. Functional interrogation of NUTM1 fusions reveals a dual oncogenic role: they drive commitment toward the B-lymphoid lineage while concurrently conferring potent leukemic stem cell properties. Strikingly, expression of a representative fusion, BRD9-NUTM1, is sufficient to induce serially transplantable B-cell progenitor, prepro-B-like leukemia in vivo, faithfully recapitulating the key molecular and immunophenotypic features of human NUTM1-r B-ALL. Mechanistically, NUTM1 fusions establish an aberrant chromatin state, marked by global enhancement of H3K27 acetylation and the creation of distinctive open chromatin regions that co-opt both B-lineage and stemness-related transcriptional programs, including those involving NF-κB and posterior HoxA genes. In stark contrast to resistant KMT2A-rearranged leukemias, NUTM1-r leukemic cells exhibit a profound sensitivity to chemotherapy. This vulnerability is mechanistically linked to the leukemia's dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, revealing specific vulnerabilities that rationalize their favorable clinical outcomes and suggest opportunities for modified therapeutic strategies.