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1685 Bone Marrow-Derived BRAFV600E-Mutated Cells Drive Neurodegeneration in a Mouse Model of Langerhans Cell Histiocytosis

Program: Oral and Poster Abstracts
Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

C. Matthias Wilk, MD1*, Jessica LeBerichel, B.S.1*, Flurin Cathomas, MD2*, George Heaton, PhD3*, Orsolya Török, MD, PhD4*, Aymeric Silvin, PhD5*, Zhenyu Yue, PhD3*, Scott Russo, PhD2*, Florent Ginhoux, PhD5,6*, Jennifer Picarsic, MD7*, Carl E. Allen, MD, PhD8 and Miriam Merad, MD, PhD1,9*

1Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Precision Immunology Institute, New York, NY
2Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, Brain & Body Research Center, Friedman Brain Institute, New York, NY
3Icahn School of Medicine at Mount Sinai, Friedman Brain Institute, New York, NY
4University of Pécs, Medical School, Department of Neurology, Pécs,, Hungary
5Inserm U1015, Gustave Roussy Cancer Campus, Villejuif, France
6Singapore Immunology Network, Singapore, SGP
7University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh O, Pittsburgh, PA
8Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, TX
9Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Progressive neurodegeneration is a devastating and ultimately fatal complication in some survivors of multi-system high-risk Langerhans Cell Histiocytosis (LCH). Patients often develop LCH-ND years after the diagnosis and successful treatment of their systemic disease, and mechanisms that underlie LCH-ND remain largely undefined. BRAFV600E+ myeloid cells have been identified in areas of active neurodegeneration. However, it is unclear if the cell of origin of this disease is mutated microglia or circulating peripheral LCH cells invading the brain tissue. Embryonic origin (e.g. microglia) versus hematopoietic origin (or both) is a critical question to be able to identify, prevent and cure LCH-ND. We therefore tested the ability of bone marrow (BM)-derived BRAFV600E cells to migrate to the brain in a mouse model.

We used BM chimera to study the transition of BRAFV600E-mutated cells to the brain as well as mechanisms of neurologic damage therein. Therefore, WT mice were conditioned with head-shielded Total Body Irradiation (TBI) and transplanted with BM from SCLCre-ER-TxBRAFV600ExRosa26YFP [LCH chimera] or SCLCre-ER-TxBRAFWTxRosa26YFP [control chimera]. Cre-recombination was induced after an engraftment period of 4 weeks. Mice were analyzed 4 months after Tamoxifen induction.

LCH chimera exhibit a parenchymal infiltration with BM-derived BRAFV600E+ macrophages 4 months after Cre-recombination while control chimera do not have substantial numbers of reporter-tagged cells in the brain. The localization pattern of BRAFV600E+ macrophages in the brain recapitulate the pattern observed in humans, i.e. in the Brain Stem and Cerebellum. BM-derived BRAFV600E+ macrophages accumulate at the interface between the bloodstream and the central nervous system (CNS) parenchyma with 10-fold higher frequency than BM-derived BRAFWT macrophages and are associated with signs of local inflammation, astrocyte activation and decline in Purkinje cell density. Finally, LCH chimera exhibit signs of neurologic impairment (e.g. ataxia, decreased strength) that was partially reversed by targeted treatment.

We conclude that BRAFV600E+ BM-derived myeloid progenitors reproducibly invade brain parenchyma where they differentiate into macrophages and induce inflammation and CNS injury. These novel insights inform previously unrecognized pathogenic mechanisms for LCH, with clinical implications in predicting LCH-ND risk, surveillance strategies, and novel therapeutic opportunities. Further, these data demonstrate potential for MAPK activation in hematopoietic myeloid progenitors to drive CNS inflammation and neurodegeneration, which may impact a broad range of neuropathological conditions beyond LCH.

Disclosures: Allen: Electra Therapeutics: Consultancy; Sobi, Inc.: Consultancy.

*signifies non-member of ASH