Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1987 Dec;84(23):8563–8567. doi: 10.1073/pnas.84.23.8563

Human heavy-chain variable region gene family nonrandomly rearranged in familial chronic lymphocytic leukemia.

A Shen 1, C Humphries 1, P Tucker 1, F Blattner 1
PMCID: PMC299585  PMID: 3120193

Abstract

We have identified a family of human immunoglobulin heavy-chain variable-region (VH) genes, one member of which is rearranged in two affected members of a family in which the father and four of five siblings developed chronic lymphocytic leukemia. Cloning and sequencing of the rearranged VH genes from leukemic lymphocytes of three affected siblings showed that two siblings had rearranged VH genes (VHTS1 and VHWS1) that were 90% homologous. The corresponding germ-line gene, VH251, was found to be part of a small (four gene) VH gene family, which we term VHV. The DNA sequence homology to VHWS1 (95%) and VHTS1 (88%) and identical restriction sites on the 5' side of VH confirm that rearrangement of VH251 followed by somatic mutation produced the identical VH gene rearrangements in the two siblings. VHTS1 is not a functional VH gene; a functional VH rearrangement was found on the other chromosome of this patient. The other two siblings had different VH gene rearrangements. All used different diversity genes. Mechanisms proposed for non-random selection of a single VH gene include developmental regulation of this VH gene rearrangement or selection of a subpopulation of B cells in which this VH has been rearranged.

Full text

PDF
8567

Images in this article

8564Image
on p.8564
8565Image
on p.8565

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blattner W. A., Strober W., Muchmore A. V., Blaese R. M., Broder S., Fraumeni J. F., Jr Familial chronic lymphocytic leukemia. Immunologic and cellular characterization. Ann Intern Med. 1976 May;84(5):554–557. doi: 10.7326/0003-4819-84-5-554. [DOI] [PubMed] [Google Scholar]
  2. Cleary M. L., Meeker T. C., Levy S., Lee E., Trela M., Sklar J., Levy R. Clustering of extensive somatic mutations in the variable region of an immunoglobulin heavy chain gene from a human B cell lymphoma. Cell. 1986 Jan 17;44(1):97–106. doi: 10.1016/0092-8674(86)90488-5. [DOI] [PubMed] [Google Scholar]
  3. Cory S., Adams J. M. Deletions are associated with somatic rearrangement of immunoglobulin heavy chain genes. Cell. 1980 Jan;19(1):37–51. doi: 10.1016/0092-8674(80)90386-4. [DOI] [PubMed] [Google Scholar]
  4. Erikson J., Finan J., Tsujimoto Y., Nowell P. C., Croce C. M. The chromosome 14 breakpoint in neoplastic B cells with the t(11;14) translocation involves the immunoglobulin heavy chain locus. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4144–4148. doi: 10.1073/pnas.81.13.4144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  6. Fraumeni J. F., Jr, Vogel C. L., DeVita V. T. Familial chronic lymphocytic leukemia. Ann Intern Med. 1969 Aug;71(2):279–284. doi: 10.7326/0003-4819-71-2-279. [DOI] [PubMed] [Google Scholar]
  7. Griffiths G. M., Berek C., Kaartinen M., Milstein C. Somatic mutation and the maturation of immune response to 2-phenyl oxazolone. Nature. 1984 Nov 15;312(5991):271–275. doi: 10.1038/312271a0. [DOI] [PubMed] [Google Scholar]
  8. Gunz F. W., Veale A. M. Leukemia in close relatives--accident or predisposition? J Natl Cancer Inst. 1969 Mar;42(3):517–524. [PubMed] [Google Scholar]
  9. Hieter P. A., Maizel J. V., Jr, Leder P. Evolution of human immunoglobulin kappa J region genes. J Biol Chem. 1982 Feb 10;257(3):1516–1522. [PubMed] [Google Scholar]
  10. Kodaira M., Kinashi T., Umemura I., Matsuda F., Noma T., Ono Y., Honjo T. Organization and evolution of variable region genes of the human immunoglobulin heavy chain. J Mol Biol. 1986 Aug 20;190(4):529–541. doi: 10.1016/0022-2836(86)90239-1. [DOI] [PubMed] [Google Scholar]
  11. Kudo A., Ishihara T., Nishimura Y., Watanabe T. A cloned human immunoglobulin heavy chain gene with a novel direct-repeat sequence in 5' flanking region. Gene. 1985;33(2):181–189. doi: 10.1016/0378-1119(85)90092-7. [DOI] [PubMed] [Google Scholar]
  12. Loenen W. A., Blattner F. R. Lambda Charon vectors (Ch32, 33, 34 and 35) adapted for DNA cloning in recombination-deficient hosts. Gene. 1983 Dec;26(2-3):171–179. doi: 10.1016/0378-1119(83)90187-7. [DOI] [PubMed] [Google Scholar]
  13. Matthyssens G., Rabbitts T. H. Structure and multiplicity of genes for the human immunoglobulin heavy chain variable region. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6561–6565. doi: 10.1073/pnas.77.11.6561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  15. Neuland C. Y., Blattner W. A., Mann D. L., Fraser M. C., Tsai S., Strong D. M. Familial chronic lymphocytic leukemia. J Natl Cancer Inst. 1983 Dec;71(6):1143–1150. [PubMed] [Google Scholar]
  16. Newkirk M. M., Mageed R. A., Jefferis R., Chen P. P., Capra J. D. Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region gene segments. J Exp Med. 1987 Aug 1;166(2):550–564. doi: 10.1084/jem.166.2.550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Parslow T. G., Blair D. L., Murphy W. J., Granner D. K. Structure of the 5' ends of immunoglobulin genes: a novel conserved sequence. Proc Natl Acad Sci U S A. 1984 May;81(9):2650–2654. doi: 10.1073/pnas.81.9.2650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Perlmutter R. M., Kearney J. F., Chang S. P., Hood L. E. Developmentally controlled expression of immunoglobulin VH genes. Science. 1985 Mar 29;227(4694):1597–1601. doi: 10.1126/science.3975629. [DOI] [PubMed] [Google Scholar]
  19. Plater-Zyberk C., Maini R. N., Lam K., Kennedy T. D., Janossy G. A rheumatoid arthritis B cell subset expresses a phenotype similar to that in chronic lymphocytic leukemia. Arthritis Rheum. 1985 Sep;28(9):971–976. doi: 10.1002/art.1780280903. [DOI] [PubMed] [Google Scholar]
  20. Putnam F. W., Florent G., Paul C., Shinoda T., Shimizu A. Complete amino acid sequence of the Mu heavy chain of a human IgM immunoglobulin. Science. 1973 Oct 19;182(4109):287–291. doi: 10.1126/science.182.4109.287. [DOI] [PubMed] [Google Scholar]
  21. Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
  22. Rechavi G., Ram D., Glazer L., Zakut R., Givol D. Evolutionary aspects of immunoglobulin heavy chain variable region (VH) gene subgroups. Proc Natl Acad Sci U S A. 1983 Feb;80(3):855–859. doi: 10.1073/pnas.80.3.855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rimm D. L., Horness D., Kucera J., Blattner F. R. Construction of coliphage lambda Charon vectors with BamHI cloning sites. Gene. 1980 Dec;12(3-4):301–309. doi: 10.1016/0378-1119(80)90113-4. [DOI] [PubMed] [Google Scholar]
  24. Takahashi N., Tetaert D., Debuire B., Lin L. C., Putnam F. W. Complete amino acid sequence of the delta heavy chain of human immunoglobulin D. Proc Natl Acad Sci U S A. 1982 May;79(9):2850–2854. doi: 10.1073/pnas.79.9.2850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tsujimoto Y., Jaffe E., Cossman J., Gorham J., Nowell P. C., Croce C. M. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature. 1985 May 23;315(6017):340–343. doi: 10.1038/315340a0. [DOI] [PubMed] [Google Scholar]
  26. Yancopoulos G. D., Desiderio S. V., Paskind M., Kearney J. F., Baltimore D., Alt F. W. Preferential utilization of the most JH-proximal VH gene segments in pre-B-cell lines. Nature. 1984 Oct 25;311(5988):727–733. doi: 10.1038/311727a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES