Grants Awarded

BRAF V600E-Drive Mouse Model of Langerhans Cell Histiocytosis

Principal Investigator
Gayane Badalian Very
Dana-Farber Cancer Institute – Boston, Massachusetts USA

Date of Award
December 2011

Amount of Award

Layperson Summary
Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects children. Cells of the immune system,
called Langerhans cells (LCs), accumulate in various organs and cause damage, in severe cases even leading
to death. We have evidence that a specific genetic abnormality called BRAF V600E appears in the majority of
cases. We now want to prove that this abnormality causes the disease and that blocking the abnormality can
treat it. We will do this using mouse models One model carries the mutation in all cells including the precursor
cells of LCs and the second model carried the mutation only in differentiated LCs. Mice in the first model
develop LCH-like disease along with several other malignancies which interfered with our monitoring, while
mice in second model developed growth retardation along with mild symptoms but no characteristic findings of
LCH. We propose refining the first model by transplanting the bone marrow cells carrying mutant BRAF into
otherwise healthy mice. This will eliminate other abnormalities that are irrelevant to our question. We can then
use these mice to test the effect of new drugs that inhibit mutant BRAF to determine their ability to treat the
LCH-like disease. A positive effect will justify a clinical trial of these inhibitors in LCH. We will also interrogate
our models for presence of additional genomic abnormalities to detect new potential targets. Once we detect
any recurrent alteration we will later verify them on the clinical samples derived from patients and plan for
future studies to determine the importance of these alterations in pathogenesis of the disease.

Twelve Month Report