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275 ALL-R: An Anchoring Score to Predict Relapse in Acute Lymphoblastic Leukemia (ALL) Using a Zebrafish Patient-Derived Xenograft Model

Program: Oral and Poster Abstracts
Type: Oral
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: The Multimodal Future: AI Approaches to Drug Development, Classification and Outcomes
Hematology Disease Topics & Pathways:
Research, Assays, Translational Research, Biological Processes, Emerging technologies, Technology and Procedures, Pathogenesis, Imaging
Saturday, December 7, 2024: 3:00 PM

Anja Arner, Dr. rer. nat1*, Bradley Wayne Blaser, MD, PhD2, Andreas Ettinger, PhD3*, Bettina Schmid, Dr. rer. nat4*, Irmela Jeremias, MD5 and Vera Binder-Blaser, Dr. med.6*

1Pediatric Hematology/Oncology, Dr. von Hauner Children’s Hospital, Munich, Germany
2Division of Hematology, The Ohio State University Wexner Medical Center, Columbus, OH
3Institute of Epigenetics and Stem Cells, Helmholtz Centre Munich, German Research Center for Environmental Health, Munich, Germany
4German Center For Neurodegenerative Diseases (DZNE), Munich, Germany
5Research Unit Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Munich, German Research Center for Environmental Health (HMGU), Munich, Germany
6Pediatric Hematology/Oncology, Dr. von Hauner Children's Hospital, Munich, Germany

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Prognosis after initial diagnosis is good; however, patients suffering from relapse have a poor outcome. The tumor microenvironment is recognized as an important factor for disease relapse but little is known about the molecular mechanisms that are involved in this process.

To study microenvironment-mediated mechanisms of relapse development in ALL, we established a larval zebrafish xenotransplantation model that allows the analysis of Leukemic cells (LCs) within an orthotopic niche using time-lapse confocal microscopy.

LCs from ALL patients experiencing early relapse (ER) or no relapse (NR) collected at the time of initial diagnosis were transplanted into zebrafish embryos. LCs homed, engrafted and proliferated within the caudal hematopoietic tissue (CHT), the hematopoietic niche at the larval stage. Migration patterns within the CHT area were quantified over 12-24 hours in a semi-automated workflow. ER-LCs migrated significantly slower compared to NR LCs (12% reduction in frame-to-frame velocity). Maximum distance traveled by ER-LCs within the niche was significantly less (by 13%), compared to NR LCs. In addition, total displacement was significantly decreased by 17 % for ER-LCs, altogether indicating more restricted movement of ER LCs within the niche, and suggesting the presence of important cell-cell interactions. An anchoring score (ALL-R score) was developed to quantify the migration behavior based on velocity, maximum distance traveled, displacement, confinement ratio and straight-line speed. The ALL-R score for ER patients was significantly higher compared to that for NR patients (Mann-Whitney test, p≤0.01).

These findings suggest the application of the ALL-R score as a relapse-prognostic factor in ALL at the time of initial diagnosis.

To understand the molecular basis for these potential interactions, we performed single cell RNA-sequencing on the ER and NR samples used in the study. Gene expression profiling of LCs and monocytes in ER and NR patients revealed: 1) ER LCs were enriched for expression of adhesion molecules such as CXCR4 (log2fc 2.012288; P-value 0.030) compared to NR LCs, 2) predicted cell-cell interactions (using CellChat) were strongest between ER LCs and ER monocytes and 3) MIF-CD74/CXCR4 and CD99-PILRA were the top-scoring ligand-receptor pairs between these groups of cells.

These data suggest that early relapse in ALL may be related to enhanced LC-niche interactions via specific monocyte signaling pathways. Ongoing work is evaluating whether disruption of these pathways might be beneficial to prevent relapse in ALL.

Disclosures: Jeremias: Tubulis GmbH: Patents & Royalties: pending patent application FLT3-mAb 20D9.

*signifies non-member of ASH