-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2705 VLA-4 Agonist Enhances the Capacity of HSC Engraftment and Immune Reconstitution

Program: Oral and Poster Abstracts
Session: 506. Bone Marrow Microenvironment: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, genomics, drug development, hematopoiesis, Therapies, Biological Processes, multi-systemic interactions
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Xianmin Song, phd1, Qiaomei He1*, Xi Sun1*, Fang Zhang2*, Pengran Wang3* and Yan Zhang, PhD4*

1Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2Shanghai Jiaotong University School of Medicine, Shanghai, China
3Department of Hematology, Shanghai, CHN
4Department of Hematology, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, CHN

Poor donor cell implantation and delayed hematopoietic reconstitution are important factors affecting the prognosis of patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, our understanding of the critical endogenous signals that reconstitute hematopoiesis in transplant patients remains limited,which is essential for achieving targeted interventions and preventing donor-recipient chimeric states after transplantation. Here, we revealed the reconstitution dynamics of human allogeneic hematopoietic stem and progenitor cells (HSPCs) and immune cell subpopulations in the post-transplantation mixed donor chimerism (MDC) to fully donor chimerism (FDC) state at single-cell resolution. The hematopoietic stem cell (HSC) implantation process involves extensive interactions with immune cells mainly through surface Kcnq5, Itga4 (encoding a subunit of VLA-4), Tfrc, CD44 receptor, and ligands for Rps19, B2m, etc. Further identification of VLA-4(integrin α4β1) as a potential regulatory target for HSC implantation by single-cell sequencing of a stable allogeneic bone marrow transplantation (Allo-BMT) MDC-FDC mouse model. Grafts Itgα4 and Itgβ1 deletion impair donor implantation and further diminish the efficacy of donor lymphocyte infusion (DLI) following Allo-BMT, rather than directly affecting DLI. Critically, we identified a VLA-4 agonist that promotes donor implantation in the mixed chimeric mouse model of Allo-BMT in a time-dependent manner, with the most pronounced promotion of early T cell implantation in particular. Moreover, it was found to enhance the self-renewal capacity of HSC and lymphoid reconstitution in competitive transplantation and human umbilical cord blood transplantation xenograft experiments. Fortunately, VLA-4 agonist does not exacerbate the acute graft-versus-host disease(aGVHD) process while maintaining the graft-versus-leukemia (GVL) effect. VLA-4 agonist not only upregulates of both Itgα4 and Itgβ1 expression, but also promotes the ERK/2 phosphorylation pathway, which affects HSC biological functions, and this process can be inhibited by ERK kinase inhibitors. These results provide insights into the regenerative process of transplanted HSPCs in human patients,and demonstrate a previously unknown positive regulation of HSC engraftment and immune reconstitution by VLA-4, and allow for a new and simple translational strategy to enhance HSC transplantation.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH