Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity

J Clin Invest. 2005 Jun;115(6):1636-43. doi: 10.1172/JCI24387. Epub 2005 May 2.


B cell chronic lymphocytic leukemia (CLL) is a disease of expanding monoclonal B cells whose B cell receptor (BCR) mutational status defines 2 subgroups; patients with mutated BCRs have a more favorable prognosis than those with unmutated BCRs. CLL B cells express a restricted BCR repertoire including antibodies with quasi-identical complementarity-determining region 3 (CDR3), which suggests specific antigen recognition. The antigens recognized by CLL antibodies may include autoantigens since about half of CLL B cells produce autoreactive antibodies. However, the distribution of autoreactive antibodies between Ig heavy-chain variable-unmutated (IgV-unmutated) CLL (UM-CLL) and IgV-mutated CLL (M-CLL) is unknown. To determine the role of antibody reactivity and the impact of somatic hypermutation (SHM) on CLL antibody specificity, we cloned and expressed in vitro recombinant antibodies from M- and UM-CLL B cells and tested their reactivity by ELISA. We found that UM-CLL B cells expressed highly polyreactive antibodies whereas most M-CLL B cells did not. When mutated nonautoreactive CLL antibody sequences were reverted in vitro to their germline counterparts, they encoded polyreactive and autoreactive antibodies. We concluded that both UM-CLLs and M-CLLs originate from self-reactive B cell precursors and that SHM plays an important role in the development of the disease by altering original BCR autoreactivity.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Autoantibodies / genetics
  • B-Lymphocytes* / metabolism
  • B-Lymphocytes* / pathology
  • Base Sequence
  • Cell Lineage / genetics*
  • Cohort Studies
  • Complementarity Determining Regions / biosynthesis
  • Complementarity Determining Regions / genetics*
  • Female
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Molecular Sequence Data
  • Neoplastic Stem Cells* / pathology
  • Receptors, Antigen, B-Cell / biosynthesis
  • Receptors, Antigen, B-Cell / genetics*
  • Somatic Hypermutation, Immunoglobulin / genetics


  • Autoantibodies
  • Complementarity Determining Regions
  • Receptors, Antigen, B-Cell