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
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.
See more of: Oral and Poster Abstracts