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CancerGenetics

• Investigation of the Association Between HLA (HLA-A, B, DRB1) Alleles and Susceptibility to Acute Lymphoblastic Leukemia in Southern Iran

• Fatemeh Mirzaei,^1,* kurush kalantar ,² Andishe mosafa ,³ Farzad Gandhari,⁴
  1. Shiraz university of medical immunology
  2. Shiraz university of medical sciences
  3. Shiraz university of medical immunology
  4. Shiraz university of medical sciences
  
  
  
• Introduction: Acute lymphoblastic leukemia (ALL) is a malignant disorder of the bone marrow characterized by the uncontrolled proliferation of immature lymphoid cells. It primarily affects children but also occurs in adults, representing the most common type of childhood cancer and accounting for approximately 25% of pediatric oncology cases. ALL arises from genetic and epigenetic alterations in precursor B or T lymphocytes, leading to impaired differentiation, increased proliferation, and resistance to apoptosis. Despite advances in therapy that have markedly improved survival rates, particularly in children, challenges remain in managing relapse and optimizing treatments for adult patients. The human leukocyte antigen (HLA) system plays a significant role in the immunobiology of ALL. As a key component of the major histocompatibility complex (MHC), HLA molecules regulate immune recognition by presenting antigens to T lymphocytes. In the context of ALL, specific HLA alleles and haplotypes have been implicated in disease susceptibility, immune surveillance, and treatment response. However, the relationship between HLA polymorphisms and ALL susceptibility—especially in Middle Eastern populations—remains incompletely characterized. This study investigates the association of classical resolution HLA A, HLA B, and HLA DRB1 alleles with ALL risk in a large cohort from southern Iran, encompassing both pediatric and adult patients.
• Methods: In this case-control study, 380 patients diagnosed with ALL (122 pediatric and 258 adult cases) were enrolled based on the 2016 World Health Organization diagnostic criteria. An equal number of healthy, unrelated individuals matched by age and sex served as controls. Genomic DNA was extracted from 10 mL of venous blood collected in sterile EDTA tubes using the Behgen DNA extraction kit. HLA typing of the HLA A, HLA B, and HLA DRB1 loci was performed using a low-resolution polymerase chain reaction with sequence-specific primers (PCR SSP) kit (BAG Health Care, Lich, Germany). This PCR SSP method employs oligonucleotide primers designed to tolerate 3′ end mismatches, enabling specific amplification when there is a near exact match with the target DNA sequence. Amplified PCR products were separated by agarose gel electrophoresis, which distinguishes DNA fragments by size. The resulting bands were visualized, photographed, and analyzed to determine allelic diversity. Differences in allele frequencies between patient and control groups were assessed using Pearson’s chi square test. Subsequently, multivariate logistic regression analyses evaluated the association between individual HLA alleles and ALL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) quantified risk. All statistical analyses were performed using SPSS version 27 (IBM/SPSS Inc., New York, USA). A p value ≤ 0.05 was considered statistically significant
• Results: Among pediatric patients, the HLA A11 allele was significantly less frequent in ALL cases than in controls (18.03% vs. 28.69%; p = 0.049; OR = 0.55, 95% CI: 0.30–1.00), suggesting a protective effect. In contrast, HLA B14 was enriched in childhood ALL patients (10.66% vs. 3.28%; p = 0.04; OR = 3.52, 95% CI: 1.10–11.00), indicating increased susceptibility. No significant associations were observed for HLA DRB1 alleles or common haplotypes in this group. In adults, distinct immunogenetic patterns emerged. Frequencies of HLA A26 (6.59% vs. 13.95%; p = 0.01; OR = 0.43) and HLA B41 (3.10% vs. 8.14%; p = 0.01; OR = 0.36) were lower in ALL patients, suggesting age-specific protective alleles. Additionally, HLA DRB4 was more frequent in adult ALL cases (31.78% vs. 20.93%; p = 0.01; OR = 1.76), pointing to a possible role for class II alleles in adult leukemia susceptibility. Again, no significant associations were detected with other HLA DRB1 alleles or haplotypes. Notably, HLA genotype did not correlate with clinical outcomes—remission status, relapse, or overall survival—indicating that while HLA polymorphisms influence ALL susceptibility, they do not appear to affect disease progression or prognosis in this population.
• Conclusion: This study highlights significant associations between specific HLA polymorphisms and ALL susceptibility in a southern Iranian cohort, with distinct immunogenetic profiles observed in pediatric versus adult patients. HLA A11 may confer protection, while HLA B14 predisposes children to ALL. In adults, HLA A26 and HLA B41 appear protective, whereas HLA DRB4 increases disease risk. However, the absence of associations with clinical outcomes—including remission, relapse, and overall survival—suggests that HLA typing may serve primarily as a biomarker of disease susceptibility rather than as a prognostic indicator. Further studies are warranted to confirm these findings and clarify the underlying immunological mechanisms
• Keywords: cute lymphoblastic leukemia; HLA; HLA A; HLA B; HLA DRB1