Type: Oral
Session: 603. Lymphoid Oncogenesis: Basic: Molecular Insights into Acute Lymphoblastic Leukemias
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Lymphoid Leukemias, ALL, Acute Myeloid Malignancies, Translational Research, Diseases, Immunology, Lymphoid Malignancies, Metabolism, Biological Processes, Pathogenesis
The functional properties of CNS-derived lineage-negative LPCs were explored in both miR overexpressing KMT2A-AFF1+ infant leukaemia models. Phenotypic analysis of the leukaemia blasts in both models showed that all populations of leukaemia present in the bone marrow (BM) were present in the CNS niche, suggesting a lack of niche-specific entry bias. Transplantation of CNS-derived LPCs demonstrated lineage-specific differences. In contrast to the pro-B ALL model, where all CNS-derived LPCs engrafted in the BM niche and resulted in terminal leukaemia, in the mixed lineage leukaemia model, engraftment of CNS-derived LPCs was significantly impaired with few transplant recipients developing terminal leukaemia. We speculate that CNS-derived KMT2A-AFF1+ mixed lineage infant leukaemia LPCs undergo irreversible adaptation to the CNS niche that may limit their ability to result in systemic relapse, unlike the more plastic adaptations that occur to the CNS niche in pro-B ALL LPCs.
We then performed transcriptomic comparisons between BM and CNS-derived LPCs from our infant leukaemia models. These comparisons have particular novelty and insight into CNS-leukaemia biology in mixed lineage leukaemia as no comparable human or murine datasets exist to our knowledge. Although there was evidence of niche-dependent regulation of some shared biological processes between the two models, there were very few common differentially expressed genes. The small number of shared differentially expressed genes included potentially targetable pathways such as the upregulation of growth factor receptors Met and Pdgfrb and the transcriptional repressor Bcl6 by CNS-derived LPCs.
In both models, CNS-derived LPCs demonstrated altered lipid and cholesterol metabolism, although through the regulation of different pathways. These metabolic adaptations in the pro-B ALL model shared many features with published data from B-ALL xenograft models (Savino et al. Nat Cancer 2020; Cousins et al. Leukemia 2022). Unique to this immunocompetent model system was the differential expression of genes implicated in leukaemia-immune cell interactions and suppression of T-cell activity. This was also lineage-specific. CNS-derived LPCs from the mixed lineage leukaemia model upregulated the immune checkpoints Btla and Cd83, whereas CNS-derived LPCs from the pro-B ALL model upregulated the immune checkpoints Ctla4 and Cd96.
Differentially regulated processes by niche unique to the mixed lineage leukaemia model included hypoxia response, IL2 STAT signalling and inflammatory signalling through TNF via NFkB. With the inherent plasticity of KMT2A-AFF1+ infant leukaemia, these lineage-specific adaptations to the CNS niche may provide a route for leukaemia cell survival and should be considered in the development of novel CNS leukaemia-specific therapies in this context.
Disclosures: Halsey: Autolus: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy.