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2696 Single Cell Profiling of Hematopoietic Stem and Progenitor Cells in Pediatric Acquired Aplastic Anemia

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Acquired: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, Bone Marrow Failure Syndromes, Aplastic Anemia, Hematopoiesis, Diseases, Biological Processes, Pathogenesis
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Derek Chan, MD, PhD1,2, Meltem Omur, MS3,4*, Diana Lin, MSc5*, Wyeth Wasserman, PhD3,4*, Aly Karsan, MD, FRCPC5,6 and Suzanne Vercauteren, MD, PhD, FRCPC6,7

1The Hospital for Sick Children, Toronto, ON, Canada
2Division of Haematology/Oncology, Department of Paediatrics, University of Toronto, Toronto, ON, Canada
3Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada
4Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
5Canada’s Michael Smith Genome Sciences Centre, BC Cancer Research Centre, Vancouver, BC, Canada
6Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
7British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada

Acquired severe aplastic anemia (AA) is a bone marrow failure disorder featuring a paucity of blood cells that significantly predisposes affected individuals to life threatening infections and/or bleeding, evolution to myelodysplastic syndrome/leukemia, risk of treatment relapse and/or death. The latest successful addition of Eltrombopag, a unique thrombopoietin receptor agonist, to frontline immunosuppressive therapy among adult patients with acquired AA has provided proof-of-principle that there may be additional ways to recover hematopoiesis in this setting. To examine the causes of and to identify novel strategies to rescue haematopoiesis in pediatric AA, we employed single cell profiling using cellular indexing of transcriptomes and epitopes (CITE-seq) on lineage-negative and treatment-naïve diagnostic severe paediatric AA (n = 5) and age-approximated healthy donor (n = 4) primary bone marrow samples and obtained transcriptomes of 2,009 and 13,861 single cells respectively. This profiling uncovered a widespread loss of primitive hematopoietic stem and progenitor cells (HSPCs) in pediatric AA with significant enrichment for IFN-γ, IL6/JAK/STAT, unfolded protein response and PI3K/AKT/MTOR pathways. Residual HSCs in pediatric AA showed enrichment of a recently described HSC inflammatory memory transcriptional signature. Granzymes were distinctly upregulated in residual HSPCs within pediatric AA. Further profiling of additional samples is required to capture additional events among rare HSPC populations. Altogether, these results demonstrate significant underlying inflammation and rationalize testing of Ruxolitinib, Sirolimus and granzyme blockade in pediatric AA. Future work will involve establishing a bone marrow organoid model of pediatric AA for therapeutic screening and drug discovery.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH