IGHV gene rearrangements as outcome predictors for CLL patients: experience of Ukrainian group

Abstract

Important characteristics of chronic lymphocytic leukaemia (CLL) cells are biased immunoglobulin variable heavy chain (IGHV) gene repertoire and expression of stereotyped B-cell receptors (BCRs); however, their prognostic value (in contrast to the impact of IGHV gene mutational status) is less clear. To evaluate the impact of separate IGHV gene usage and expression of stereotyped BCRs in CLL prognosis. Clinical data and IGHV gene configuration were analysed in 319 consecutive patients with CLL. We found that the majority of clinical parameters of patients were defined by IGHV mutational status. Our data also provided new evidence supporting the prognostic relevance of separate IGHV genes or stereotyped BCR in CLL, namely: (a) a restricted non-mutated (UM) IGHV gene repertoire in CLL patients with autoimmune haemolytic anaemia (AIHA) (more frequent expression of UM IGHV1-69, IGHV3-11 and IGHV4-59 genes, P = 0.001), a shorter period of AIHA development for expressors of these genes (P = 0.001) and a tendency towards expression of a stereotypic HCDR3 (P = 0.029), (b) a high incidence of second solid tumour development in IGHV3-21-expressing patients (P = 0.005) and (c) differences in overall survival (OS) of UM CLL patients depending on the BCR structure. Further research of specific IGHV gene usage and subsets of stereotyped BCRs in CLL may be helpful in more precise prediction of CLL prognosis in individual patients.

Mutation Status and Immunoglobulin Gene Rearrangements in Patients from Northwest and Central Region of Spain with Chronic Lymphocytic Leukemia

“…Studies from Asia [21, 22], South America [23], and Europe [12, 26] showed a low representation of IGHV3-11 subfamily, with a similar proportion of M-CLL and U-CLL in this subgroup. However, the Ukrainian group showed that its presence was associated with an increased risk of developing autoimmune hemolytic anemia [25]. Interestingly, in our cohort, IGHV3-11 gene was significantly overused in the unmutated group and was associated with a lower OS ( P = 0.025), but we failed to find a relationship with the risk of developing autoimmune hemolytic anemia.…”

“…The higher usage of IGHV1-69 has been reported in Ukrainian [25] and Mediterranean [12] CLL patients. In accordance with these observations, IGHV1-69 was also the most frequently used segment of IGHV1 family in our studied population and the second most commonly detected in the global series (21 cases, 9.4%).…”

“…This has led to extensive investigations on the mutational status and IGHV gene usage in different populations of patients diagnosed with CLL over the last few years. Results from these studies suggest that the presence of ethnic variations and geographic background may affect IGHV gene usage, in CLL [21–25]. …”

Cancers after Chornobyl: From Epidemiology to Molecular Quantification

“…Higher frequencies (89.3%) of unmutated immunoglobulin variable heavy chain (IGHV) genes were shown among 28 cleanup workers from 1986 with CLL, in comparison with 68.1% in 238 nonexposed CLL patients. In a later study, the same group of investigators failed to demonstrate any difference [40]. Comparison of genome changes in general exposed population vs. nonexposed one in the post-Chornobyl period describes upregulation of MYC , HNF1A , and HNF4A and YWHAG , NF-κB1, and SP1 , together with a downregulation of CEBPA , YWHAG , SATB1 , and RB1 [41].…”

Effect of IGHV Gene Mutation Status and BCR Structure Stereotypy on Effectiveness of BR Regimen in First-Line Therapy of Chronic Lymphocytic Leukemia

“…Частота использования гена IGHV3-21 составила 7,7 % (n = 14), что примерно соответствует частоте, выявленной в популяции пациентов из Украины (5,8 %) [16]. В то же время это меньше, чем в сканди-навской когорте (11,7 %), и больше, чем в американ-ской (2,6 %) и средиземноморской (2,9 %) популяциях [17,18].…”