Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research, Diseases, Immune Disorders, white blood cell disorders, Myeloid Malignancies
BRAFV600E expression was enforced through Cre-mediated recombination to create BRAFV600ECD11c and BRAFV600EMSaA3 mice. Mice were analyzed at weeks 5, 10, 25, and 52 for body and organ weights and histology. Tissues were characterized by immunohistochemistry, gene expression, Luminex, CYTOF and RNASeq.
BRAFV600ECD11c mice exhibited a more aggressive phenotype than BRAFV600EMS4A3 counterparts, though both developed systemic histiocytic infiltration. Kinetics of organomegaly, histiocytic infiltration, and systemic inflammation was much slower in the BRAFV600EMS4a3 mice. Notably, BRAFV600EMS4a3 demonstrated increased enrichment of CD207-negative macrophages in spleen, liver and bone marrow. BRAFV600EMS4a3 mice readily survived past 52 weeks, while BRAFV600ECD11c had 100% mortality by 16 weeks. Bulk RNASeq and Ingenuity Pathway Analysis identified relative decrease in macrophage functionality in BRAFV600EMSaA3 mice. Additionally, macrophage infiltrate was observed in heart, major blood vessels and kidneys of BRAFV600EMS4a3 where these organs were not affected in BRAFV600ECD11c.
The same mutation that creates an aggressive LCH-like phenotype in CD11c-derived cells creates an indolent ECD-like phenotype in monocyte-derived cells. This study demonstrates a critical role for ontogeny in pathogenesis of histiocytic disorders. Further, the BRAFV600EMS4a3 mouse provides an ECD model for pre-clinical testing of therapeutic strategies.
Disclosures: McClain: SOBI Corporation: Membership on an entity's Board of Directors or advisory committees. Allen: Electra Therapeutics: Consultancy; Sobi, Inc.: Consultancy.
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