Hollmén:
Clever-1 is a previously unrecognized checkpoint of hematopoietic stem cell regeneration
Maija Hollmén, PhD,
Disclosure: Please see Session Details (link below).
Background: Chemotherapy-induced myelosuppression remains the major dose-limiting toxicity of cancer therapy, yet no targeted therapy directly promotes hematopoietic regeneration. Clever-1 (STAB1), a scavenger receptor best known for its immunosuppressive role in macrophages, is targeted by the anti-Clever-1 antibody bexmarilimab, currently in clinical trials for myeloid malignancies. Whether Clever-1 regulates hematopoiesis has not been investigated.
Results: We identified Clever-1 expression in murine multipotent progenitors, common lymphoid progenitors, and bone marrow sinusoidal endothelial cells. Analysis of human single-cell datasets demonstrated STAB1 expression in a subset of CD34+ hematopoietic stem and progenitor cells (HSPCs), enriched for transcriptional programs associated with stem cell self-renewal. STAB1 expression was induced by inflammatory stimulation, identifying Clever-1 as an inflammation-responsive receptor on human HSPCs.
To determine its functional role, we performed single-cell RNA sequencing of bone marrow following prolonged anti-Clever-1 treatment. Clever-1 blockade suppressed quiescence-associated immediate-early response programs while inducing MYC- and E2F-driven proliferation in long-term HSCs. Granulocyte-macrophage progenitors upregulated mitotic programs, accompanied by transcriptional features consistent with emergency granulopoiesis.
These molecular changes translated into enhanced hematopoietic output. Clever-1 knockout mice exhibited increased steady-state platelet counts despite normal platelet lifespan and activation, indicating enhanced platelet production rather than altered clearance. Consistently, Clever-1-deficient bone marrow generated more multilineage colonies and nearly six-fold more megakaryocyte progenitors ex vivo, findings reproduced by bexmarilimab treatment of human cord blood CD34+ cells.
Following myeloablative injury with 5-fluorouracil, both genetic deletion and antibody-mediated blockade of Clever-1 accelerated recovery of multiple hematopoietic populations. Anti-Clever-1 treatment similarly enhanced platelet regeneration after antibody-induced thrombocytopenia, demonstrating improved hematopoietic recovery across independent injury models.
Conclusions: We identify Clever-1 as a previously unrecognized regulator of hematopoietic stem and progenitor cells that restrains regenerative hematopoiesis. Genetic deletion or antibody-mediated blockade releases this checkpoint, promoting stem cell activation, megakaryopoiesis, and recovery following hematopoietic injury. Given that bexmarilimab is already in clinical development for MDS and AML, these findings reveal a dual mechanism whereby Clever-1 blockade may simultaneously enhance anti-tumor immunity and accelerate hematologic recovery, supporting its development as a regenerative therapy for treatment-induced myelosuppression.