MDS-Associated Spliceosome Mutations Regulate Host Defense

ABSTRACT
Myelodysplastic Syndrome (MDS) is a hematopoietic stem cell disorder characterized by myeloid cell
differentiation defects and dysplastic blood cell production. The majority of MDS patients die of disease related
causes, with infection or infectious complications being the most common cause. While it is known that myeloid
cells exhibit functional defects in MDS patients, the extent and cause of these defects remain unclear and the
corresponding effects on host defense have received limited study. With the advent of next-generation
sequencing technology, analysis of somatically-acquired mutations in patient samples has become a normal
part of clinical practice in MDS patients. Interestingly, the most common class of mutations found in MDS
patients are mutations in various components of the spliceosome. We have determined that these MDS-
associated spliceosome gene mutations lead to alterations in innate immune signaling pathways and
compromise the function of myeloid cells in mouse models of spliceosome-mutated MDS. This leads to a
significant defect in host defense. Based on these preliminary studies, we have hypothesized that MDS
patients with spliceosome mutations are at an increased risk of infection because of immune dysfunction in
their myeloid cells. To test this hypothesis, we will investigate the effects of spliceosome mutations on host
defense using: (1) ex vivo studies with mouse and human neutrophils, (2) ex vivo studies with mouse and
human macrophages, and (3) in vivo studies in mice expressing mutant spliceosome genes and in an analysis
of clinical data from patients with MDS. These studies will determine the mechanisms underlying host defense
defects in MDS patients with spliceosome mutations and will provide important clinical data about patient risk
stratification.

Grant Number: 5R01AI155749-05
NIH Institute/Center: NIH
Principal Investigator: Scott Alper