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4318 Myeloid Progenitors Define Extent of Disease in Mouse Models of Histiocytic Disorders: BRAFV600E Expression in Monocyte Lineage Recapitulates Erdheim-Chester Phenotype

Program: Oral and Poster Abstracts
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
Monday, December 12, 2022, 6:00 PM-8:00 PM

C. Matthias Wilk, MD1*, Brooks Scull, MS2*, Ryan Fleischmann, MS2*, Tsz-Kwong Man, PhD3*, Kenneth L. McClain, MD, PhD4, Miriam Merad, MD, PhD5*, Florent Ginhoux, PhD6* and Carl E. Allen, MD, PhD7

1Precision Immunology Institute and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
2Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX
3Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX
4Texas Childrens Cancer and Hematology Centers, Houston, TX
5Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY
6Singapore Immunology Network ( SIgN), Agency for Science, Technology and Research ( A *STAR), Singapore, Singapore
7Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, TX

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by granulomatous lesions with CD207+ dendritic cells associated with a wide spectrum of clinical presentations. Activating MAPK pathway genes (most frequently BRAFV600E) are identified in lesion DCs as well as in precursor cells in bone marrow and peripheral blood in some cases. LCH typically arises in children, but can also occur de novo in adults. Erdheim-Chester disease (ECD) is a related histiocytic disorder characterized by CD163+ histiocytic lesions with activating MAPK mutations (most frequently BRAFV600E) arising primarily in adults. Unlike LCH, ECD lesion distribution frequently includes kidneys and heart. In order to test the impact of cell of origin on disease phenotype, we developed Cre-inducible mouse models in which BRAFV600E expression is enforced at distinct stages of differentiation: BRAFV600ECD11c and BRAFV600EMSaA3. ITGAX/CD11c is expressed across a range of myeloid dendritic cell and monocyte lineages, where MS4a3 is expressed exclusively in GMPs and GMP-derived cells (e.g. monocytes).

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.

*signifies non-member of ASH