# Lineages and pathophysiology of clonal histiocytic disorders

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $712,850

## Abstract

Project Summary
This project aims to characterize at the molecular, cellular and organismal levels the pathophysiology of clonal
histiocytic disorders, exemplified by Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD).
These diseases display a considerable heterogeneity in terms of prognostic and clinical presentation, and are
characterized by the occurrence of neurodegenerative syndromes and liver and lung fibrosis, the mechanisms
of which are mysterious. Their pathophysiology is largely unknown. Two recent discoveries offer an opportunity
to re-evaluate the pathophysiology and molecular underpinning of clonal histiocytic disorders, improve their
diagnostic, prognostic, and offer new therapeutic strategies. First, the discovery of somatic mutations of the
RAS-ERK pathway in >70% of cases of LCH and ECD by us and others has led to new therapeutic
approaches based on the use of BRAF inhibitors and has renewed interests in efforts toward solving the
pathophysiology of these diseases. Second, an important revision of our understanding of myeloid
development stems from recent works from our laboratory and others which have revealed that the tissue-
resident macrophages found in adult mice originate from early hematopoietic progenitors from the yolk sac
independent of hematopoietic stem cells (HSCs) and persist within their tissue of residence in adults.
Following on this work, we made the novel hypothesis that somatic BRAF mutations in yolk sac progenitors
may causes histiocytoses and we have developed in vivo models that allow to test this hypothesis
experimentally. Our preliminary results indicate that conditional expression of a BRAFV600E allele in yolk sac
hematopoietic progenitors in vivo does results in the accumulation of BRAFV600E macrophage clones in various
tissues, and is responsible in particular for a neurodegenerative syndrome in adult mice, that recapitulates for
the first time one of the most intriguing and adverse phenotypic characteristics of the human histiocytic
neoplasms.
We will (Aim 1) will investigate the molecular and cellular mechanisms that underlie the development of brain
neurodegenerative disease and identify molecular pathways that drive pathological histiocytes, (Aim 2)
determine the pathological roles of BRAFV600E macrophages outside the brain in vivo and in particular in liver
fibrosis, and (Aim 3) investigate the efficiency of BRAF inhibitor administration in the murine models.
These experiments will provide a proof of concept that a mutations in yolk sac progenitors can cause an
histiocytic disease in adults, help elucidate the pathophysiology and mechanism of histiocytoses and some of
their most adverse complication such as the neurodegenerative syndrome, and reveal novel therapeutic
targets to be used in conjunction with, or alternatively to, BRAF inhibitors.

## Key facts

- **NIH application ID:** 10001080
- **Project number:** 5R01HL138090-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Frederic Geissmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $712,850
- **Award type:** 5
- **Project period:** 2017-08-16 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001080

## Citation

> US National Institutes of Health, RePORTER application 10001080, Lineages and pathophysiology of clonal histiocytic disorders (5R01HL138090-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10001080. Licensed CC0.

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