Contributions
Abstract: PB1775
Type: Publication Only
Background
The mutational status of the immunoglobulin heavy variable (IGHV) genes is established as one of the most important prognostic molecular genetic markers in chronic lymphocytic leukemia (CLL). It divides the CLL patients into two subsets with a different clinical course, mutated (M-CLL) and unmutated (U-CLL). U-CLL is delineated with a cutoff value of 98% identity with the closest germ line of IGHV genes. The shaping of the CLL IGVH gene repertoire depends on a different genetic background and effects of the environmental factors. In addition, a strong bias in the use of individual genes and subgroups between normal and malignant B-cells and presence of highly homologous “stereotyped” heavy complementary-determining region 3 (VH-CD3) is shown, which suggests the role of a specific antigen in the pathogenesis of the disease.
Aims
In this study, we analyzed the mutation status and pattern of IGHV, IGHD and IGHJ gene usage in Macedonian CLL patients.
Methods
Ninety-seven consecutive CLL patients that presented at the University Clinic of Hematology –Skopje in the period between 2011-2013, were included in the study. IGHV mutation status and gene repertoire were analyzed using the reverse transcriptase– polymerase chain reaction (RT-PCR) and sequencing methodology. The mutational status of the IGVH genes was determined using two databases: IMGT/V-QUEST tool and IgBLAST software. The stereotyped subset assignment was performed using ARResT/AssignSubset tool (Bioinformatics Analysis Team).
Results
We found that 44.3% of the cases belonged to M-CLL and 55.7% to U-CLL, with a progressive disease dominant in the U-CLL subset. Both groups were comparable regarding the age and gender distribution. Only 39% of the M-CLL patients presented with a progressive disease, compared to 74% of the U-CLL patients (p<0.05).The comparison of median time to the first treatment (TTT) between M-CLL and U-CLL (39 months versus 8 months, respectively) showed a statistically significant difference between the groups (p<0.01).
Conclusion
Our study showed a strong correlation between IGHV gene mutational status and clinical course of CLL. Results on IGHV-IGHD-IGHJ genes usage in our study are comparable to the previously reported from Mediterranean countries. The high frequency of V1-69gene and low frequency of IGVH3-21 in our CLL patients that originate from a small geographic region further promotes the geographic bias in the use of IGVH genes and points to an important role in antigen stimulation in the pathogenesis of the CLL subsets. Our findings indicated a lower expression of the stereotyped BCR region than those previously reported (~30%), but they were comparable with the results reported for the Serbian CLL patients (10.1% versus 15,3%, respectively), in the only previous published study of this kind from Western Balkans.
Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology
Keyword(s): IgH rearrangment, Chronic Lymphocytic Leukemia
Abstract: PB1775
Type: Publication Only
Background
The mutational status of the immunoglobulin heavy variable (IGHV) genes is established as one of the most important prognostic molecular genetic markers in chronic lymphocytic leukemia (CLL). It divides the CLL patients into two subsets with a different clinical course, mutated (M-CLL) and unmutated (U-CLL). U-CLL is delineated with a cutoff value of 98% identity with the closest germ line of IGHV genes. The shaping of the CLL IGVH gene repertoire depends on a different genetic background and effects of the environmental factors. In addition, a strong bias in the use of individual genes and subgroups between normal and malignant B-cells and presence of highly homologous “stereotyped” heavy complementary-determining region 3 (VH-CD3) is shown, which suggests the role of a specific antigen in the pathogenesis of the disease.
Aims
In this study, we analyzed the mutation status and pattern of IGHV, IGHD and IGHJ gene usage in Macedonian CLL patients.
Methods
Ninety-seven consecutive CLL patients that presented at the University Clinic of Hematology –Skopje in the period between 2011-2013, were included in the study. IGHV mutation status and gene repertoire were analyzed using the reverse transcriptase– polymerase chain reaction (RT-PCR) and sequencing methodology. The mutational status of the IGVH genes was determined using two databases: IMGT/V-QUEST tool and IgBLAST software. The stereotyped subset assignment was performed using ARResT/AssignSubset tool (Bioinformatics Analysis Team).
Results
We found that 44.3% of the cases belonged to M-CLL and 55.7% to U-CLL, with a progressive disease dominant in the U-CLL subset. Both groups were comparable regarding the age and gender distribution. Only 39% of the M-CLL patients presented with a progressive disease, compared to 74% of the U-CLL patients (p<0.05).The comparison of median time to the first treatment (TTT) between M-CLL and U-CLL (39 months versus 8 months, respectively) showed a statistically significant difference between the groups (p<0.01).
Conclusion
Our study showed a strong correlation between IGHV gene mutational status and clinical course of CLL. Results on IGHV-IGHD-IGHJ genes usage in our study are comparable to the previously reported from Mediterranean countries. The high frequency of V1-69gene and low frequency of IGVH3-21 in our CLL patients that originate from a small geographic region further promotes the geographic bias in the use of IGVH genes and points to an important role in antigen stimulation in the pathogenesis of the CLL subsets. Our findings indicated a lower expression of the stereotyped BCR region than those previously reported (~30%), but they were comparable with the results reported for the Serbian CLL patients (10.1% versus 15,3%, respectively), in the only previous published study of this kind from Western Balkans.
Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology
Keyword(s): IgH rearrangment, Chronic Lymphocytic Leukemia