Grants Awarded

Principal Investigator:
Randy Cron 
University of Alabama at Birmingham 
Brimingham, AL USA 

Date of Award:
December 2023
Award Amount:
$50,000

Layperson Summary:

Macrophage activation syndrome (MAS) is related to a group of disorders called hemophagocytic lymphohistiocytosis (HLH), characterized by overly active white blood cells, including histiocytes. Although the genetic or familial form of HLH is rare affecting approximately only one in 50,000 live births, the secondary or acquired forms of HLH (sHLH) and MAS are much more common and can occur at any age of life. It may be that as many as 20% of the general population possess a genetic risk factor for MAS/sHLH, as many of these children and adults have single copy defects/mutations in the same genes responsible for fHLH, which results early in life from gene mutations of both chromosome copies. Both fHLH and sHLH/MAS are frequently fatal conditions requiring aggressive chemotherapy and/or immunosuppression, with high risks of infection and death, but only 30-40% of patients have identifiable genetic risk.

Recently, we identified mutations from sHLH/MAS patients in genes not previously associated with sHLH/MAS. These 2 related genes, DOCK2 and DOCK8, are important for the killing function of certain white blood cell populations (T lymphocytes and natural killer cells). Preliminary data suggest these patient-derived mutations in DOCK2 and DOCK8 disrupt lymphocyte killing function resulting in excess inflammation (cytokines) responsible for the multi-organ failure as part of sHLH/MAS. We have identified several mutations, particularly in DOCK8, suggesting this may be a commonly disrupted gene among individuals with the histiocytic disorder of sHLH/MAS. This implies that DOCK2 and DOCK8 genes be included in the list of genes to be sequenced when identifying individuals with sHLH/MAS.

We further plan to study the effects of these DOCK2 and DOCK8 mutations on how they contribute to sHLH/MAS disease processes. Identifying disrupted interactions with protein binding partners involved in mutant DOCK2 and DOCK8 effects on lymphocyte function may yield novel disease mechanism insights and potentially novel sHLH/MAS genetic contributors. A better understanding of the number of individuals with genetic risk factors for sHLH/MAS, as well as knowledge of how these mutations contribute to this histiocytic disease, will help identify individuals at risk and tailor appropriate therapy to those who develop sHLH/MAS.

This project was supported by the Histiocytosis Association of Canada (HAC) in the amount of $25,000 USD