HLA system affects the age‐at‐onset in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) occurs from childhood to old age. The adult form is characterized by the presence of Philadelphia chromosome resulting from bcr/abl translocation. The BCR-ABL fusion proteins are immunogenic, and the junctional sequences show unique HLA class I and class II restriction patterns in vitro. A previous study in the west of Scotland showed an influence of several HLA genotypes on the age-at-onset of CML. In the present study, we examined the HLA-A, -B, and -DRB1/3/4/5 allele and haplotype distributions in Turkish CML patients diagnosed in a single center where they are routinely HLA-typed by PCR-SSP analysis as a preparation for stem cell transplantation. The patients were 169 subjects of age 17-60 years. The older patients were not HLA typed and missing from the study group. The age-matched control group (n = 213) was healthy blood donors from the same geographical area. HLA-B*37 showed a risk association with CML [P = 0.02; odds ratio (OR) = 5.35]. The DRB1*10 association at similar magnitude was due to its linkage disequilibrium (LD) with B*37. HLA-B*35 and DRB1*11 showed independent protective effects (P = 0.007 and 0.017; OR = 0.54 and 0.60, respectively). The protective association of DRB1*11 may be due to its involvement in the presentation of the common (b3a2) fusion gene. HLA-B*14 and DRB1*01 showed strong LD, and all 5 patients who were positive for the presumed haplotype B*14-DRB1*01 were of age 43 years old or older (P = 0.003), suggesting a delay effect. We also examined the influence of homozygosity for DRB3 (DR52) and DRB4 (DR53) haplotypes on susceptibility. As previously shown in CML and CLL, DRB4 homozygosity was a risk marker (P = 0.01; OR = 3.36), and DRB3 homozygosity was protective (P = 0.007; OR = 0.51). Despite the lack of elderly patients in the study group, the opposite accelerating (DRB4) and delaying (DRB3) effects of homozygous genotypes on the age-at-onset were evident. Besides replicating previously found associations in a different population, this study also suggested new, and probably population-specific associations in CML. The mechanisms by which the HLA system modifies susceptibility to CML are unknown, likely to include immune and nonimmune ones, and worthy of further studies. Am. J. Hematol. 73:256-262, 2003.

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk

“…The SNP near the HLA-DRA gene, rs2395185, is a marker for the HLA-DRB4 (DR53) lineage [23]. The HLA-DRB4 lineage or its marker SNP have been previously shown as a risk marker in lung cancer [27], asthma [29], rheumatoid arthritis [28], type I diabetes [44], adult acute myeloblastic leukemia [45], chronic myeloid leukemia [46], chronic lymphoid leukemia [47][48][49] and in childhood ALL (males only) [24,50,51], and as a protective marker for non-Hodgkin lymphoma [26], and ulcerative colitis [30][31][32]52]. The DRB4/DR53 lineage has been shown previously to have a risk association with childhood ALL, with male specificity, within a European sample via HLA typing [24].…”

Reply to Verheyden and Demanet

“…In our study, we used human leukocyte antigen (HLA)-matched bone marrow donors as a representative control group, considering that (i) HLA genotype is associated with the occurrence and the age-at-onset of CML 3,4 and (ii) KIR-HLA ligand interactions appear to play a role in the pathogenesis of leukemia.…”

Human leukocyte antigens HLA DRB1 influence clinical outcome of chronic lymphocytic leukemia

“…2 The Human Leukocyte Antigen complex (HLA) is one of the inherited factors that influences the development of B-CLL and clinical outcome of diffuse large B-cell lymphoma. [3][4][5] This led us to examine whether HLA antigens contribute to the clinical course of CLL.…”