Grants Awarded

H Syndrome as a Model for Rare Histiocytoses

Principal Investigator:
Ruthy Shiloh PhD.
and Sarah Elitzur MD
Schneider Children’s Medical Center
Petach Tikva, Israel

Date of Award:
December 2023
Amount of Award:

Layperson Summary:

Histiocytoses are disorders characterized by the abnormal accumulation of specialized blood cells (called histiocytes) in body tissues and organs that may lead to severe disability and death. A significant advance has been made with the discovery that many histiocytic tumors are caused by mutations in genes which “turn on” a tumor growth pathway called the MAPK pathway. These tumors can be treated using targeted MAPK-directed therapy. However, in many cases such mutations are not identified and the mechanisms that cause the disease are not understood. To address this gap, we studied patients with H syndrome, a rare hereditary disorder which predisposes to histiocytosis by an unknown mechanism.

H syndrome is caused by hereditary mutations in a gene that encodes the protein ENT3. ENT3 functions in cells as a transporter of nucleosides, which are the building blocks of DNA and RNA. In a preliminary study of a group of patients with H syndrome we found that the dysfunctional ENT3 transporter leads to accumulation of nucleosides, which “turn on” the MAPK pathway through special nucleoside-sensing receptors and induce inflammation and histiocytosis. We also show that in one of our patients, treatment with a drug that blocks the MAPK pathway led to the complete resolution of a histiocytic tumor. The importance of this study is that it demonstrates a novel, alternative mechanism leading to histiocytosis and enables us to study it closely. We now plan to further establish this model by performing additional detailed molecular studies of the mechanism leading to histiocytosis in these patients. In addition, we wish to address the lack of information on patients with H syndrome and their response to different therapies by forming a comprehensive international clinical database which will include clinical characteristics, treatment strategies and outcomes.

Understanding the molecular pathways leading to histiocytosis in patients with H syndrome and elucidating patients’ patterns of response to therapeutic agents would significantly improve treatment options for these patients and contribute to our understanding of the pathogenesis and treatment of rare histiocytoses.