DOI: http://dx.doi.org/10.18203/2320-6012.ijrms20160783

Gene repertoire of IGHV-IGHD-IGHJ rearrangements in Macedonian patients with chronic lymphocytic leukemia-single centre experience

Sanja Trajkova

Abstract


Background: B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with many patients surviving for decades with watch and wait strategy or no treatment, whereas others surrender to their disease despite therapy. In recent years, new molecular prognostic factors came to light that have significantly improved the stratification of the CLL patients. One of the most important molecular predictors, the immunoglobulin VH gene mutational status, divides CLL into two prognostic groups, depending on the presence or absence of somatic hypermutation, where unmutated U-CLL are associated with  remarkably worse prognosis than mutated U-CLL. The aim of the study was evaluation of rearrangement of IG genes profile in Macedonian CLL patients in line with facts that there are some geographic linked variations in IG genes.

Methods: In this study, mutational status and configuration of IGHV-IGHD-IGHJ rearrangements in 70 treatment naïve CLL patients were analyzed using reverse transcriptase– polymerase chain reaction (RT-PCR) and sequencing methodology at the center for bimolecular pharmaceutical analyses, faculty of pharmacy, Skopje, Macedonia.

Results: Our evaluation have shown that 52.8% patients belonged to the U-CLL subset, whereas 47.1% belonged to the M-CLL subset. The most frequently expressed IGHV subgroup was IGHV3 (41.4%), followed by IGHV1 and IGHV4 (28.5%), IGHV5 (1.4%). In the IGHD and IGHJ sets most frequently expressed was IGHD3 (55.7%), IGHJ6 gene (37.1%) respectively.

Conclusions: Our evaluation of mutational status on IGVH, IGDH, and IGJH gene in Macedonian CLL patients resulted with data which are consubstantial to those from Mediterranean area and West Balkan.

 


Keywords


Chronic lymphocytic leukemia, Prognosis, Mutational status

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References


Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219-34.

Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198-206.

Jelinek DF, Tschumper RC, Geyer SM, Bone ND, Dewald GW, Hanson CA, et al. Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukaemia. Br J Haematol. 2001;115:854-61.

Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukemia. Lancet. 2004;363:105-11.

Krober A, Bloehdorn J, Hafner S, Bühler A, Seiler T, Kienle D et al. Additional genetic high-risk features such as 11qdeletion, 17 deletion and V3-21 usage characteristic discordance of ZAP-70 and VH mutation status in chronic lymphocitic leukemia. J Clin Oncol. 2006;24:969-75.

Stiegenbauer S, Bullinger L, Lichter P, Döhner H; German CLL Study Group (GCLLSG). Chronic lymphocytic leukemia. Genetics of chronic lymphocitic leukemia: genomic aberration and VH mutation status in pathogenesis and clinical course. Leukemia. 2002;16:993-1007.

Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stella S, Guida G et al. Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene. Blood. 2005;105:1678-85.

Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004;200:519-25.

Panovska-Stavridis I, Cevreska L, Stojanovic A, Efremov D. Prognostic value of immunoglobulin variable heavy chain gene mutation status: long term follow-up in a series of chronic lymphocytic leukemia patients. Prilozi. 2006;26(2):127-37.

Mauerer K, Zahrieh D, Gorgun G, Li A, Zhou J, Ansén S et al. Immunoglobulin gene segment usage, location and immunogenicity in mutated and unmutated chronic lymphocytic leukaemia. Br J Haematol. 2005;129:499-510.

Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T, et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood. 2007;109:259-70.

Tobin G, Thunberg U, Karlsson K, Murray F, Laurell A, Willander K, et al. Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood. 2004;104:2879-85.

Panovska-StavridisI, Ivanovski M, Siljanovski N, Cevreska L, Efremov GD. Chronic lymphocytic leukemia patients with a V1-69 gene rearrangement do not have inferior survival with respect to patients that express other unmutated V(H) genes. Leukemia Res. 2007;31(2):245-8.

Bomben R, Dal Bo M, Capello D, Benedetti D, Marconi D, Zucchetto A, et al. Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study. Blood. 2007;109:2989-98.

Tobin G, Söderberg O, Thunberg U, Rosenquist R. V(H)3-21 gene usage in chronic lymphocytic leukemia—characterization of a new subgroup with distinct molecular features and poor survival. Leuk Lymphoma. 2004;45:221-8.

Karan-Djurasevic T, Palibrk V, Kostic T, Spasovski V, Nikcevic G, Srzentic S, et al. Mutational Status and Gene Repertoire of IGHV-IGHD- IGHJ Rearrangements in Serbian Patients With Chronic Lymphocytic Leukemia. Clin Lymphoma Myeloma Leuk. 2012;12(4):252-60.