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. 1981 Nov;78(11):7096–7100. doi: 10.1073/pnas.78.11.7096

Developmental hierarchy of immunoglobulin gene rearrangements in human leukemic pre-B-cells.

S J Korsmeyer, P A Hieter, J V Ravetch, D G Poplack, T A Waldmann, P Leder
PMCID: PMC349202  PMID: 6273911

Abstract

We have used a special class of human acute lymphocytic leukemias, the common "non-T/non-B" cell type, to define a hierarchy of genetic rearrangements that occur during the earliest stages of B-cell maturation. This has allowed us to identify intermediate cells predicted by a hierarchial model in which immunoglobulin heavy chain variable region gene formation precedes that of light chain and in which kappa light chain gene formation precedes that of lambda. The model emphasizes the flexible nature of immunoglobulin gene recombination that not infrequently produces aberrant or null genes that are phenotypically excluded from expression. Remaining alleles or isotypic genes can then be utilized as "spares" undergoing recombination until a valid gene is formed. Significantly, the excluded allele or isotype is frequently deleted from the genome. In addition to defining a pathway of genetic maturation, this analysis provides a powerful means to further classify cases of non-T/non-B-cell acute lymphocytic leukemia, most of which seem to reside at early stages along the B-cell pathway of differentiation.

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Selected References

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

  1. Alt F. W., Enea V., Bothwell A. L., Baltimore D. Activity of multiple light chain genes in murine myeloma cells producing a single, functional light chain. Cell. 1980 Aug;21(1):1–12. doi: 10.1016/0092-8674(80)90109-9. [DOI] [PubMed] [Google Scholar]
  2. Alwine J. C., Kemp D. J., Parker B. A., Reiser J., Renart J., Stark G. R., Wahl G. M. Detection of specific RNAs or specific fragments of DNA by fractionation in gels and transfer to diazobenzyloxymethyl paper. Methods Enzymol. 1979;68:220–242. doi: 10.1016/0076-6879(79)68017-5. [DOI] [PubMed] [Google Scholar]
  3. Bonner W. A., Hulett H. R., Sweet R. G., Herzenberg L. A. Fluorescence activated cell sorting. Rev Sci Instrum. 1972 Mar;43(3):404–409. doi: 10.1063/1.1685647. [DOI] [PubMed] [Google Scholar]
  4. Brack C., Hirama M., Lenhard-Schuller R., Tonegawa S. A complete immunoglobulin gene is created by somatic recombination. Cell. 1978 Sep;15(1):1–14. doi: 10.1016/0092-8674(78)90078-8. [DOI] [PubMed] [Google Scholar]
  5. Brodsky F. M., Parham P., Barnstable C. J., Crumpton M. J., Bodmer W. F. Monoclonal antibodies for analysis of the HLA system. Immunol Rev. 1979;47:3–61. doi: 10.1111/j.1600-065x.1979.tb00288.x. [DOI] [PubMed] [Google Scholar]
  6. Brouet J. C., Preud'homme J. L., Penit C., Valensi F., Rouget P., Seligmann M. Acute lymphoblastic leukemia with pre-B-cell characteristics. Blood. 1979 Jul;54(1):269–273. [PubMed] [Google Scholar]
  7. Brouet J. C., Seligmann M. The immunological classification of acute lymphoblastic leukemias. Cancer. 1978 Aug;42(2 Suppl):817–827. doi: 10.1002/1097-0142(197808)42:2+<817::aid-cncr2820420703>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  8. Chessells J. M., Hardisty R. M., Rapson N. T., Greaves M. F. Acute lymphoblastic leukaemia in children: Classification and prognosis. Lancet. 1977 Dec 24;2(8052-8053):1307–1309. doi: 10.1016/s0140-6736(77)90361-0. [DOI] [PubMed] [Google Scholar]
  9. Coleclough C., Cooper D., Perry R. P. Rearrangement of immunoglobulin heavy chain genes during B-lymphocyte development as revealed by studies of mouse plasmacytoma cells. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1422–1426. doi: 10.1073/pnas.77.3.1422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Cory S., Jackson J., Adams J. M. Deletions in the constant region locus can account for switches in immunoglobulin heavy chain expression. Nature. 1980 Jun 12;285(5765):450–456. doi: 10.1038/285450a0. [DOI] [PubMed] [Google Scholar]
  12. Early P., Huang H., Davis M., Calame K., Hood L. An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH, D and JH. Cell. 1980 Apr;19(4):981–992. doi: 10.1016/0092-8674(80)90089-6. [DOI] [PubMed] [Google Scholar]
  13. Fröland S. S., Natvig J. B. Class, subclass, and allelic exclusion of membrane-bound Ig of human B lymphocytes. J Exp Med. 1972 Aug 1;136(2):409–414. doi: 10.1084/jem.136.2.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Haynes B. F., Mann D. L., Hemler M. E., Schroer J. A., Shelhamer J. H., Eisenbarth G. S., Strominger J. L., Thomas C. A., Mostowski H. S., Fauci A. S. Characterization of a monoclonal antibody that defines an immunoregulatory T cell subset for immunoglobulin synthesis in humans. Proc Natl Acad Sci U S A. 1980 May;77(5):2914–2918. doi: 10.1073/pnas.77.5.2914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hieter P. A., Korsmeyer S. J., Waldmann T. A., Leder P. Human immunoglobulin kappa light-chain genes are deleted or rearranged in lambda-producing B cells. Nature. 1981 Apr 2;290(5805):368–372. doi: 10.1038/290368a0. [DOI] [PubMed] [Google Scholar]
  16. Hieter P. A., Max E. E., Seidman J. G., Maizel J. V., Jr, Leder P. Cloned human and mouse kappa immunoglobulin constant and J region genes conserve homology in functional segments. Cell. 1980 Nov;22(1 Pt 1):197–207. doi: 10.1016/0092-8674(80)90168-3. [DOI] [PubMed] [Google Scholar]
  17. Honjo T., Kataoka T. Organization of immunoglobulin heavy chain genes and allelic deletion model. Proc Natl Acad Sci U S A. 1978 May;75(5):2140–2144. doi: 10.1073/pnas.75.5.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hozumi N., Tonegawa S. Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc Natl Acad Sci U S A. 1976 Oct;73(10):3628–3632. doi: 10.1073/pnas.73.10.3628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Janossy G., Bollum F. J., Bradstock K. F., McMichael A., Rapson N., Greaves M. F. Terminal transferase-positive human bone marrow cells exhibit the antigenic phenotype of common acute lymphoblastic leukemia. J Immunol. 1979 Oct;123(4):1525–1529. [PubMed] [Google Scholar]
  20. Kataoka T., Kawakami T., Takahashi N., Honjo T. Rearrangement of immunoglobulin gamma 1-chain gene and mechanism for heavy-chain class switch. Proc Natl Acad Sci U S A. 1980 Feb;77(2):919–923. doi: 10.1073/pnas.77.2.919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kurosawa Y., von Boehmer H., Haas W., Sakano H., Trauneker A., Tonegawa S. Identification of D segments of immunoglobulin heavy-chain genes and their rearrangement in T lymphocytes. Nature. 1981 Apr 16;290(5807):565–570. doi: 10.1038/290565a0. [DOI] [PubMed] [Google Scholar]
  22. Leder P., Max E. E., Seidman J. G., Kwan S. P., Scharff M., Nau M., Norman B. Recombination events that activate, diversify, and delete immunoglobulin genes. Cold Spring Harb Symp Quant Biol. 1981;45(Pt 2):859–865. doi: 10.1101/sqb.1981.045.01.103. [DOI] [PubMed] [Google Scholar]
  23. Levitt D., Cooper M. D. Mouse pre-B cells synthesize and secrete mu heavy chains but not light chains. Cell. 1980 Mar;19(3):617–625. doi: 10.1016/s0092-8674(80)80038-9. [DOI] [PubMed] [Google Scholar]
  24. Maki R., Kearney J., Paige C., Tonegawa S. Immunoglobulin gene rearrangement in immature B cells. Science. 1980 Sep 19;209(4463):1366–1369. doi: 10.1126/science.6774416. [DOI] [PubMed] [Google Scholar]
  25. Max E. E., Seidman J. G., Leder P. Sequences of five potential recombination sites encoded close to an immunoglobulin kappa constant region gene. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3450–3454. doi: 10.1073/pnas.76.7.3450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Max E. E., Seidman J. G., Miller H., Leder P. Variation in the crossover point of kappa immunoglobulin gene V-J recombination: evidence from a cryptic gene. Cell. 1980 Oct;21(3):793–799. doi: 10.1016/0092-8674(80)90442-0. [DOI] [PubMed] [Google Scholar]
  27. Osmond D. G., Nossal G. J. Differentiation of lymphocytes in mouse bone marrow. II. Kinetics of maturation and renewal of antiglobulin-binding cells studied by double labeling. Cell Immunol. 1974 Jul;13(1):132–145. doi: 10.1016/0008-8749(74)90233-0. [DOI] [PubMed] [Google Scholar]
  28. Perry R. P., Kelley D. E., Coleclough C., Seidman J. G., Leder P., Tonegawa S., Matthyssens G., Weigert M. Transcription of mouse kappa chain genes: implications for allelic exclusion. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1937–1941. doi: 10.1073/pnas.77.4.1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Polsky F., Edgell M. H., Seidman J. G., Leder P. High capacity gel preparative electrophoresis for purification of fragments of genomic DNA. Anal Biochem. 1978 Jul 1;87(2):397–410. doi: 10.1016/0003-2697(78)90689-9. [DOI] [PubMed] [Google Scholar]
  30. Ravetch J. V., Kirsch I. R., Leder P. Evolutionary approach to the question of immunoglobulin heavy chain switching: evidence from cloned human and mouse genes. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6734–6738. doi: 10.1073/pnas.77.11.6734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Reinherz E. L., Kung P. C., Goldstein G., Levey R. H., Schlossman S. F. Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1588–1592. doi: 10.1073/pnas.77.3.1588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
  33. Ritz J., Pesando J. M., Notis-McConarty J., Lazarus H., Schlossman S. F. A monoclonal antibody to human acute lymphoblastic leukaemia antigen. Nature. 1980 Feb 7;283(5747):583–585. doi: 10.1038/283583a0. [DOI] [PubMed] [Google Scholar]
  34. Sakano H., Hüppi K., Heinrich G., Tonegawa S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature. 1979 Jul 26;280(5720):288–294. doi: 10.1038/280288a0. [DOI] [PubMed] [Google Scholar]
  35. Sakano H., Kurosawa Y., Weigert M., Tonegawa S. Identification and nucleotide sequence of a diversity DNA segment (D) of immunoglobulin heavy-chain genes. Nature. 1981 Apr 16;290(5807):562–565. doi: 10.1038/290562a0. [DOI] [PubMed] [Google Scholar]
  36. Sakano H., Maki R., Kurosawa Y., Roeder W., Tonegawa S. Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy-chain genes. Nature. 1980 Aug 14;286(5774):676–683. doi: 10.1038/286676a0. [DOI] [PubMed] [Google Scholar]
  37. Seidman J. G., Leder P. The arrangement and rearrangement of antibody genes. Nature. 1978 Dec 21;276(5690):790–795. doi: 10.1038/276790a0. [DOI] [PubMed] [Google Scholar]
  38. Seidman J. G., Max E. E., Leder P. A kappa-immunoglobulin gene is formed by site-specific recombination without further somatic mutation. Nature. 1979 Aug 2;280(5721):370–375. doi: 10.1038/280370a0. [DOI] [PubMed] [Google Scholar]
  39. Shimizu A., Takahashi N., Yamawaki-Kataoka Y., Nishida Y., Kataoka T., Honjo T. Ordering of mouse immunoglobulin heavy chain genes by molecular cloning. Nature. 1981 Jan 15;289(5794):149–153. doi: 10.1038/289149a0. [DOI] [PubMed] [Google Scholar]
  40. Siden E., Alt F. W., Shinefeld L., Sato V., Baltimore D. Synthesis of immunoglobulin mu chain gene products precedes synthesis of light chains during B-lymphocyte development. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1823–1827. doi: 10.1073/pnas.78.3.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vogler L. B., Crist W. M., Bockman D. E., Pearl E. R., Lawton A. R., Cooper M. D. Pre-B-cell leukemia. A new phenotype of childhood lymphoblastic leukemia. N Engl J Med. 1978 Apr 20;298(16):872–878. doi: 10.1056/NEJM197804202981603. [DOI] [PubMed] [Google Scholar]
  42. Waldmann T. A., Polmar S. H., Balestra S. T., Jost M. C., Bruce R. M., Terry W. D. Immunoglobulin E in immunologic deficiency diseases. II. Serum IgE concentration of patients with acquired hypogammaglobulinemia, thymoma and hypogammaglobulinemia, myotonic dystrophy, intestinal lymphangiectasia and Wiskott-Aldrich syndrome. J Immunol. 1972 Aug;109(2):304–310. [PubMed] [Google Scholar]

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