The immunoglobulin heavy chain gene (IgHV) mutation status correlates with the clinical outcome of patients with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy. Why the survival rate of patients with unmutated IgHV is worse than that of patients with mutated IgHV is unknown. CLL cells with unmutated IgHV were thought to originate from naïve B lymphocytes, whereas CLL cells with mutated IgHV were thought to arise from B cells that have undergone somatic hypermutation (SHM). Cell surface protein expression profile and gene expression studies showing that all CLL cells, regardless of their IgHV mutation status, are of postgerminal center origin, negated this hypothesis. We hereby propose that all CLL cells undergo SHM and their proliferation rate determines their IgHV mutation status. DNA breaks, accumulated during SHM, are restored by various DNA repair mechanisms. In rapidly dividing cells DNA breaks are repaired by the efficient high-fidelity homology-directed DNA repair apparatus, whereas in slowly dividing cells they are repaired by the inefficient low-fidelity nonhomology end-joining repair mechanism. Accordingly, a low IgHV mutation rate is found in rapidly dividing cells whereas a high mutation rate is typically found in slowly dividing cells. Thus, the proliferation rate of CLL cells determines the IgHV mutation status and patients’ clinical outcome.

Keywords:
Chronic lymphocytic leukemia, IgHV mutation status, Somatic hypermutation
1.
Rozovski U, Hazan-Halevy I, Keating MJ, Estrov Z: Personalized medicine in CLL: current status and future perspectives. Cancer Lett 2014; 352: 4–14.
2.
Schroeder HW Jr, Dighiero G: The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today 1994; 15: 288–294.
3.
Sagatys EM, Zhang L: Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia. Cancer Control 2012; 19: 18–25.
4.
Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chio-razzi N: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.
5.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK: Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.
6.
Lin KI, Tam CS, Keating MJ, Wierda WG, O’Brien S, Lerner S, Coombes KR, Schlette E, Ferrajoli A, Barron LL, Kipps TJ, Rassenti L, Faderl S, Kantarjian H, Abruzzo LV: Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood 2009; 113: 3168–3171.
7.
Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, O’Brien S, Gribben J, Rai K: Chronic lymphocytic leukaemia. Nat Rev Dis Primers 2017; 3: 16096.
8.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating M, Montserrat E, Chiorazzi N, Stilgenbauer S, Rai KR, Byrd JC, Eichhorst B, O’Brien S, Robak T, Seymour JF, Kipps TJ: iwCLL guidelines for diagnosis, indications for treatment, response assessment and supportive management of CLL. Blood 2018; 131: 2745–2760.
9.
Stilgenbauer S, Bullinger L, Lichter P, Dohner H; German CLL Study Group (GCLLSG): Genetics of chronic lymphocytic leukemia: genomic aberrations and VH gene mutation status in pathogenesis and clinical course. Leukemia 2002; 16: 993–1007.
10.
Oscier DG, Thompsett A, Zhu D, Stevenson FK: Differential rates of somatic hypermutation in VH genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 1997; 89: 4153–4160.
11.
Jain P, Nogueras Gonzalez GM, Kanagal-Shamanna R, Rozovski U, Sarwari N, Tam C, Wierda WG, Thompson PA, Jain N, Luthra R, Quesada A, Sanchez-Petitto G, Ferrajoli A, Burger J, Kantarjian H, Cortes J, O’Brien S, Keating MJ, Estrov Z: The absolute percent deviation of IGHV mutation rather than a 98% cut-off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine, cyclophosphamide and rituximab. Br J Haematol 2018; 180: 33–40.
12.
Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, Freedman A, Inghirami G, Cro L, Baldini L, Neri A, Califano A, Dalla-Favera R: Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 2001; 194: 1625–1638.
13.
Seifert M, Sellmann L, Bloehdorn J, Wein F, Stilgenbauer S, Durig J, Kuppers R: Cellular origin and pathophysiology of chronic lymphocytic leukemia. J Exp Med 2012; 209: 2183–2198.
14.
Damle RN, Ghiotto F, Valetto A, Albesiano E, Fais F, Yan XJ, Sison CP, Allen SL, Kolitz J, Schulman P, Vinciguerra VP, Budde P, Frey J, Rai KR, Ferrarini M, Chiorazzi N: B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood 2002; 99: 4087–4093.
15.
Patten PE, Chu CC, Albesiano E, Damle RN, Yan XJ, Kim D, Zhang L, Magli AR, Barrientos J, Kolitz JE, Allen SL, Rai KR, Roa S, Mongini PK, MacCarthy T, Scharff MD, Chiorazzi N: IGHV-unmutated and IGHV-mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions. Blood 2012; 120: 4802–4811.
16.
Liu M, Schatz DG: Balancing AID and DNA repair during somatic hypermutation. Trends Immunol 2009; 30: 173–181.
17.
Papavasiliou FN, Schatz DG: Cell-cycle-regulated DNA double-stranded breaks in somatic hypermutation of immunoglobulin genes. Nature 2000; 408: 216–221.
18.
Poltoratsky V, Heacock M, Kissling GE, Prasad R, Wilson SH: Mutagenesis dependent upon the combination of activation-induced deaminase expression and a double-strand break. Mol Immunol 2010; 48: 164–170.
19.
Branzei D, Foiani M: Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 2008; 9: 297–308.
20.
Lieber MR: The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 2010; 79: 181–211.
21.
Gine E, Martinez A, Villamor N, Lopez-Guillermo A, Camos M, Martinez D, Esteve J, Calvo X, Muntanola A, Abrisqueta P, Rozman M, Rozman C, Bosch F, Campo E, Montserrat E: Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica 2010; 95: 1526–1533.
22.
van Gent R, Kater AP, Otto SA, Jaspers A, Borghans JA, Vrisekoop N, Ackermans MA, Ruiter AF, Wittebol S, Eldering E, van Oers MH, Tesselaar K, Kersten MJ, Miedema F: In vivo dynamics of stable chronic lymphocytic leukemia inversely correlate with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow. Cancer Res 2008; 68: 10137–10144.
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2018
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