Restricted immunoglobulin VH region repertoire in chronic lymphocytic leukemia patients with autoimmune hemolytic anemia

Abstract

Between 10% and 25% of chronic lymphocytic leukemia (CLL) patients have episodes of autoimmune hemolytic anemia (AIHA) during the course of their disease. The anti-erythrocyte autoantibodies in most cases are polyclonal and express a different heavy chain isotype than the malignant clone, indicating that they are secreted by normal autoreactive B lymphocytes. To further investigate the pathogenesis of the AIHA in CLL, we analyzed the lg heavy (H) chain variable region genes expressed by leukemic cells from CLL patients with and without AIHA. Two VH genes were preferentially expressed by the leukemic cells in the CLL cases with AIHA and were present in 9 of the 12 investigated cases. The 51p1/DP-10 gene was expressed in 5 of these cases and was absent in the control group of 12 consecutive CLL cases without AIHA, whereas the DP-50 gene was present in 4 CLL-AIHA cases and only once in the control CLL group. A strikingly similar H-chain CDR3 region that contained a single reading frame of the DXP4 DH gene segment, and N- encoded proline at the DH/JH boundary, and a tyrosine-rich region encoded by the JH6 gene segment was observed in four CLL-AIHA cases. The preferential expression of two VH gene segments and a particular CDR3 region by the leukemic cells of patients with AIHA suggests that the antibodies produced by the CLL cells are directly involved in the pathogenesis of the hemolytic anemia.

Primary cutaneous B-cell lymphoma is associated with somatically hypermutated immunoglobulin variable genes and frequent use of VH1-69 and VH4-59 segments

“…In addition, a productive monoclonal VH1-69 rearrangement is present in 1AE6% of normal CD5-B lymphocytes in adults and this segment has been found preferentially rearranged in patients with B-CLL with autoimmune haemolytic anaemia. 35 In B-cell malignancies, biased VH1-69 usage has been found in 10-20% of B-CLL, most harbouring unmutated IgVH genes 36,37 and in several types of hepatitis C virusassociated BCL. 13,[38][39][40] Frequent usage of the VH1-69 gene was also reported in the salivary gland extranodal MZL of the MALT type.…”

Analysis of the immunoglobulin heavy chain gene variable region of 101 cases with peripheral B cell neoplasms and B cell chronic lymphocytic leukemia in the Japanese population

“…Many reports of somatic mutation analysis of B-CLL have been published so far: B-CLL was considered initially to lack significant hypermutation of the rearranged VH gene compared with MALT and DLBCL which have hypermutated VH genes, but CD5 ϩ B-CLL with somatically mutated VH genes have been described. [8][9][10][11][20][21][22][23][24][25] In addition, B-CLL is known to lack intraclonal diversity. Oscier et al recently reported that B-CLL with trisomy 12 showed germline sequence, while B-CLL with 13q14 showed somatic hypermutation.…”

Somatic hypermutation and VH gene usage in mantle cell lymphoma

“…A restricted usage of V H genes has been reported in different entities of B-cell lymphomas. Preferential usage of the V H 1-69 and V H 4-34 genes has been shown in B-CLL and other B-cell malignancies (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Interestingly, this non-random usage of individual V H genes has been hypothesized to reflect that the Ig structure may play a role in leukemia/lymphoma development, possibly through chronic antigen stimulation (17,20,21,23,24).…”