Abstract Myelodysplastic syndromes (MDS) are part of a heterogeneous and overlapping group of clonal
diseases that arise in the hematopoietic stem or progenitor cells and also include acute myeloid leukemia
(AML), myeloproliferative neoplasms (MPN), and the hybrid MDS/MPN entities. Individuals with MDS have a
high risk of progressing to leukemia, with approximately 30% expected to develop AML. Outcomes for MDS
are poor, with 5 year relative survival estimates below 50%, suggesting that early detection and prevention
could have a large impact. During our initial funding period, we conducted the first population-based case
control study of MDS, including recruitment of over 550 cases. In this competing renewal application, we
propose to capitalize on our well-characterized study population to investigate the contribution of genetic
variation to MDS risk and to evaluate the role of the killer cell immunoglobulin receptors (KIR) on incidence and
survival. Our specific aims are to: 1) Identify germline susceptibility variants for MDS through collaboration with
the MDS Clinical Research Consortium; 2) Evaluate the relationship between KIR haplotypes and risk of MDS;
and 3) Understand the role of KIR gene haplotypes in disease progression and survival, overall and by MDS
subtype. We hypothesize that we will identify variants that predict MDS risk and that risk estimates will be
larger in cases with high risk MDS subtypes who are more likely to progress to AML. We further hypothesize
that KIR haplotype B will be identified at a lower frequency in MDS cases compared with population controls
and that KIR haplotype A will be associated with worse prognosis. We will genotype germline DNA samples
from 465 MDS cases from our case-control study, 200 MDS cases from Moffitt Cancer Center and 1,119 age-
matched population controls using the Illumina HumanOmni2.5 array. We will use available genotyping data
from 1,700 MDS cases from the MDS Clinical Research Consortium and 4,597 healthy controls for replication
and meta-analysis. In order to improve our power to detect associations, we will restrict our analysis to regions
of open chromatin in myeloid cells as determined by ATAC-seq of primary cell cultures. For Aim 2, targeted
capture and sequencing will be used to measure variation in the 143kb region containing the KIR genes on
chromosome 19 (position 5537984-55378670). We will compare the two main KIR gene haplotype blocks (A
and B) in cases and controls. To evaluate the impact of KIR haplotypes on progression, we will treat the 457
confirmed MDS cases as a cohort and evaluate associations between KIR haplotype and progression to AML
and survival. The role of common genetic variation is largely unexplored in MDS; however, the few studies that
have been conducted provide a rationale for further evaluation. Identifying predictors of rapid death from MDS,
such as KIR haplotypes or alleles, could provide clues to the underlying biology in this subgroup and suggest
new avenues for therapy. Adoptive NK cell therapy is one such option that is already in development for
treatment of hematologic malignancy.
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