Molecular Genetic Characterization of Chronic Lymphocytic Leukemia Aggressivity in Czech Patients: A Nucleotide Variability of Genes Coding for Heavy Chain of Immunoglobulin

Overview

Background.
Chronic lymphocytic leukemia is a heterogeneous disease manifesting with a variable clinical course. It is evident from many studies, that the division into two main prognostic categories is possible on the basis of mutation status of the immunoglobulin heavy-chain gene. The objective of our work was to identify a presence or absence of IgVH gene mutations in B-CLL patients which are monitored or treated on hematological clinics and to determine the presence of individual D and J_H subgenes in malignant population of B-cells. 

Methods and Results.
A nucleotide sequence of IgVH gene of neoplastic cells was analyzed by appropriate molecular-genetic methods. RNA/cDNA was collected from 358 patients and a spectrum of individual subgenes translocations was identified. Our results show that 56.3% of patients manifested an unmutated variable (V_H) segment. It is expected from the published data that this group of patients will suffer from aggressive course of the disease and will exhibit a substantially shorter survival in comparison to patients possessing somatic hypermutations. An expanded population of leukemic B-cells showed increased occurrence of clones whose variable segments belong to three different families. V_H3 alleles are the ones most frequently used. A frequency of unmutated alleles is prominently shifted into families with V_H1 homology. The preferred „diversity and joining“ segments are D3, D2 and J_H 4 and J_H 6. 

Conclusions.
The analysis of heavy chain immunoglobulin gene after recombinant V_H-D-J_H segments translocation belongs to a standard hematooncological investigation. The results are an important prognostic criterion for prediction of expected disease aggressivity and for a minimal residual disease monitoring. 

Key words:
chronic lymphocytic leukemia, immunoglobulin heavy-chain gene (IgVH), mutation status, somatic hypermutation, prognostic factor.