Poster Presentation 38th Lorne Cancer Conference 2026

Temporal single clone analyses reveal a Xlr4b driven HSPC program that facilitates T-cell reconstitution following transplantation. (#270)

Elanor N Wainwright 1 , Ali Motazedian 1 , Enid Lam 1 , Liyang Fei 1 , Kathy Knezevic 1 , Henrietta Holze 1 , Thomas Burn 2 , Andrea Gillespie 1 , Laure Talarmain 1 , Shirom Chabra 3 , Tomoya Isobe 3 , Melania Barile 3 , Jovana Maksimovic 1 , Laura K Mackay 2 , Berthold Göttgens 3 , Alicia Oshlack 1 , Mark A Dawson 1
  1. Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia
  2. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne
  3. Cambridge Stem Cell Institute Jeffrey Cheah Biomedical Centre, Cambridge

Haematopoietic stem cell transplantation (HSCT) provides a potentially curative strategy for >100,000 paediatric and adult cancer patients worldwide each year. However, infection-related morbidity/mortality remains a major impediment, particularly until T-cell immunity is restored. Thus, there is an urgent need to discover novel approaches to accelerate T-cell production after HSPC transplantation (HSCT). Using SPLINTR-SR, an advanced lineage tracing system with expressed barcodes, we precisely delineate at single clone resolution the cell-intrinsic and microenvironmental influences on rapid HSPC engraftment and T-cell reconstitution post HSCT. Through a clone-splitting strategy, we establish that engraftment potential, lineage commitment and clonal output are cell-intrinsic properties of HSPCs. Surprisingly, pre-existing cytopenia in the host does not redirect inherent HSPC lineage commitment programs upon HSCT but instead increases the output of specific HSPC clones to cater for the lineage-deficient need. A systematic dissection of bone marrow homing and thymic seeding after HSCT revealed a rare subset of HSPC clones that have cell-intrinsic properties for rapid and high-output T-cell reconstitution. Underpinning this potential is a novel HSPC transcription program including prominent expression of an uncharacterised gene Xlr4b. Through exogenous expression of Xlr4b in HSPCs, we demonstrate a bone marrow lymphoid differentiation trajectory that preferences T-lineage reconstitution. Clonally resolved analysis thus outlines a future path to rapidly generate T-cells for a wide range of therapeutic applications.