GERMLINE PREDISPOSITION TO ACUTE LYMPHOBLASTIC LEUKEMIA: ELUCIDATING THE LINK WITH IMMUNE DYSREGULATION

Abstract

Acute Lymphoblastic Leukemia (ALL) involves uncontrolled growth of lymphoid cancer blasts and makes up 34% of pediatric cancers. While only 3-5% of pediatric cancers were previously described as linked to germline predisposition, ongoing recent extensive studies suggest 8-10% with germline predisposition links. Intriguingly, it is clinically observed that pediatric leukemias of Arabic ethnicity referred in Sidra Medicine-Qatar, are frequently accompanied by genetically driven immune dysregulation, an observation supported by genetic evidence. We sought to investigate the germline predisposition to ALL in a highly inbred pediatric Arab cohort with a focus on immune system-related genetic variations. To achieve this aim we: (1) curated a comprehensive catalog of immune- and leukemia/cancer-related genes to guide in functional cross-validation (2) identified rare, pathogenic germline variants in 226 pediatric ALL cases from Qatar and Lebanon; using whole-genome sequencing, (3) assessed variant frequency and estimated enrichment against Qatari healthy genomes, (4) assessed functional impact of the variants via pathway enrichment and 3D protein/structural modeling, and (5) integrated our WGS with pilot mRNA sequencing analyses. We identified in our cohort 5 novel variants and an additional set of biologically relevant germline variants, candidate as predisposing to leukemogenesis, in genes involved in antigen presentation, immune signaling, immune regulation and cellular integrity: TLR7, HLA-A, ANKRD55 and AHNAK2. Functional enrichment, zygosity analysis, population-based comparison, in silico protein stability assessments and a pilot transcriptional RNA-seq analyses supported the functional significance of these variants. In conclusion, our study identified a distinct landscape of rare and potentially deleterious germline variants within an underrepresented Arabic pediatric ALL cohort. These genomic variants converged upon key biological pathways in MHC-mediated antigen presentation (HLA-A), innate immune sensing (TLR7), T cell inflammation (ANKRD55) and tumor microenvironment modeling (AHNAK2) likely contributing to an environment that facilitates leukemogenesis.  

Date of Award	2026
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences