Background: Outcome in African Ancestry (AA) Acute Myelogenous Leukemia and Myelodysplastic Syndrome patients (pt) is inferior. In particular, AML data suggests differential enrichment of genomic abnormalities [i.e., lower incidence of Core binding factor AML, worse outcome among NPM1 mutated cases etc.). The immune system plays a crucial role in recognizing and eliminating cancer cells. HLA class I molecules present endogenous antigens to CD8+ T cells. HLA gene diversity possibly reflects differences in antigen presentation and immune response. Therefore, mapping HLA-I alleles used by “pathogenic variants in hematopoietic cells” during leukemogenesis may inform “prioritized MHC restricted pathways” susceptible to T cell targeting. In this study, we hypothesized that Class I alleles may be classified as disadvantageous when they do not present mutated neoantigens, promoting immune escape, and that such alleles will be differentially found in African Ancestry (AA) pt at higher frequencies compared non-AA population.

Methods: After IRB approval, 31 patients with available Class I HLA typing and clinical data were included in analysis. The mutational profile obtained by NGS was analyzed for each patient to determine mutated protein sequences for the downstream analysis of neopeptides. MHCNetPan software was used to predict MHC-neopeptide binding. To compare HLA frequencies between AA vs non-AA pt, allele frequencies were analyzed using Fisher's exact test.

Results: Median age of studied patients was 63 years (range 28-89). Fifty-one percent were males. AML and MDS were observed in 74% and 26% patients respectively. By ethnicity, 58% were non-AA and 42% were AA. The median number of mutations was 4. Studied patients had mutations in driver genes. Most mutant driver genes in our cohort were methylation genes (TET2 and DNMT3A), chromatin regulation genes (ASXL1, EZH2), transcription factors (TP53 and RUNX1). Alleles that approached “disadvantageous” significance for AA were A*11:01 (p=0.01), A*25:01 (p=0.01), B*13:02 (p=0.001), B*14:02 (p=0.0006), C*02:02 (p=<0.0001), and C*08:02 (p=0.01). Alleles approaching “advantageous” significance for AA cases: A*33:03 (p=<0.0001) and A*02:02 (p=<0.0001).

Conclusion: In conclusion, some HLA alleles, including A*11:01, A*25:01, B*13:02, B*14:02, C*02:02 and C*08:02 are more common in AA pt, suggesting that these alleles may predispose individuals to develop leukemias. On average, these alleles present “lower” number of bindings [i.e., proportion of 1, 2, 3, 5, and 6 bindings in AA vs non-AA, 26% v 72%, 23% v 77%, 0% v 100%, and 31% vs 69%, <p=0.0001]. Differential MHC frequencies in AML/MDS AA vs non-AA pt implicate the involvement of neoantigen presentation in leukemic cells. While our data requires adjustment for local “normal” allele frequencies, they could potentially be used for patient risk stratification and treatments.

Disclosures

No relevant conflicts of interest to declare.

This content is only available as a PDF.
2024
Sign in via your Institution