Tetsuhiro Fujimoto

Requirement of Runx1/AML1/PEBP2alphaB for the generation of haematopoietic cells from endothelial cells.

Recent studies revealing that endothelial cells derived from E8.5‐E10.5 mouse embryos give rise to haematopoietic cells appear to correspond to previous histological observations that haematopoietic cell clusters are attached to the ventral aspect of dorsal aorta in such a way as if they were budding from the endothelial cell layer. Gene disruption studies have revealed that Runx1/AML1 is required for definitive haematopoiesis but not for primitive haematopoiesis, but the precise stage of gene function is not yet known.

Step-wise divergence of primitive and definitive haematopoietic and endothelial cell lineages during embryonic stem cell differentiation

Background The developmental processes leading from the mesoderm to primitive and definitive haematopoietic and endothelial lineages, although of great importance, are still poorly defined. Recent studies have suggested a model in which common precursors give rise to endothelial progenitors and haematopoietic progenitors, the latter subsequently generating both primitive and definitive haematopoietic lineages. However, this model is contradicted by findings that suggest the emergence of haematopoietic cells from the endothelial lineage.

Origin of Hematopoietic Progenitors during Embryogenesis

It has been widely accepted that hematopoietic and endothelial cell lineages diverge from a common progenitor referred to as the hemangioblast. Recently, analyses of the potential of progenitor cells purified from mouse embryos as well as embryonic stem cells differentiating in vitro resolved intermediate stages between mesodermal cells and committed precursors for hematopoietic and endothelial cell lineages. There are two distinct hematopoietic cell lineages which have different origins, i.e., primitive hematopoietic lineage derived from mesoderm or hemangioblasts and definitive hematopoietic lineage derived from endothelial cells. The endothelium is suggested to provide a milieu in which the definitive hematopoietic lineage acquires multiple potentials.

All B cells are progeny of endothelial cells : a new perspective

Summary: We present here a speculative view of embryonic hematopoiesis. We do this with the hope of finding directions for future study, keeping in mind that our model may diverge from the real situation. However, we want to emphasize that previous models have neglected the possibility that endothelial cells (EC) represent a progenitor of hematopoietic cells (HPC). Emerging evidence, including our own, and previous histological studies argue for the presence of hemogenic EC. We discuss seemingly contradictory points of view of embryonic hematopoiesis, such as the origin of lymphogenic progenitors, and have shown that they may be resolved more satisfactorily by introducing this notion. Obviously, a good model should be a testable one, so we are currently developing experimental systems to demonstrate that all B cells are, indeed, the progeny of EC.

Over‐expression of c‐Myb increases the frequency of hemogenic precursors in the endothelial cell population

Definitive hematopoiesis has been proposed to arise from hemogenic endothelial cells during mouse embryogenesis. The c‐myb proto‐oncogene is essential for the development of definitive hematopoiesis and was reported to be activated in hemogenic endothelial cells. To investigate whether c‐Myb is involved in regulating the development of hemogenic endothelial cells, we conditionally induced c‐myb over‐expression during the in vitro differentiation of embryonic stem cells. VE‐cadherin+ CD45− cells inducibly expressing c‐Myb showed an increase in multilineage colony formation as well as an augmented capacity of the colony forming cells to self‐renew in vitro under the condition that only the endogenous c‐myb gene was expressed during differentiation of hematopoietic cells. Over‐expression of c‐Myb in the endothelial population led to activation of genes associated with definitive hematopoiesis such as Runx1, Hoxb4, Mll and Etv6. Our data provide evidence that c‐Myb is able to exert an effect in endothelial cells which fosters the establishment of their hemogenic potential.

Galectin-9 as a Predictive Marker for the Onset of Immune-Related Adverse Effects Associated with Anti-CCR4 MoAb Therapy in Patients with Adult T Cell Leukemia

Adult T-cell leukemia/lymphoma (ATL/ATLL) is one of the most malignant lymphomas with poor prognosis. ATL/ATLL cells express CC chemokine receptor 4, and mogamulizumab (anti-CCR4 monoclonal antibody) exhibits strong cytotoxicity for ATL/ATLL cells. We analyzed plasma samples of 6 patients with ATL/ATLL treated with chemotherapy followed by mogamulizumab therapy (mogatherapy) for changes in the levels of biomarkers in relation to immune-related adverse effects. As treatment is often associated with skin eruptions, we investigated the profiles of inflammatory cytokines, including galectin-9 (Gal-9), which becomes increased in various infectious diseases and allergic patients. Gal-9, soluble interleukin (IL)-2 receptor, tumor necrosis factor-α, and IL-10 levels were increased before chemotherapy, and Gal-9 levels were associated with the sIL-2 receptor, which reflects tumor burden. Inflammatory levels decreased after chemotherapy. After mogatherapy, 5 of 6 patients attained complete remission (CR), whereas 1 patient showed no response (NR) and died. Among 5 patients with CR, the biomarkers remained low during mogatherapy, except for a 3-5-fold increment in Gal-9 (associated with skin eruptions). A skin biopsy showed infiltration by inflammatory cells and Gal-9 synthesis in areas with CD8 cell infiltration. In the patient with NR, increased levels of Gal-9 and the aforementioned biomarkers were noted 3 days after mogatherapy, followed by opportunistic infections resembling immune reconstitution inflammatory syndrome. Therefore, an increased Gal-9 plasma level in ATL/ATLL indicates tumor burden and reflects immune activation by mogatherapy. These findings may indicate that an increase in the Gal-9 level, a novel immune checkpoint molecule, can reflect immune-related adverse effects of various biotherapies.