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. 1992 Dec 1;176(6):1577–1581. doi: 10.1084/jem.176.6.1577

Predominance of fetal type DJH joining in young children with B precursor lymphoblastic leukemia as evidence for an in utero transforming event

PMCID: PMC2119455  PMID: 1460419

Abstract

The presence of N sequences in the complementarity determining region 3 (CDR3) of the rearranged immunoglobulin H chain is developmentally regulated: N regions are generally present in the DJH joinings of adult B cells but are often absent in fetal B cells. Analysis of the CDR3 in 61 B precursor acute lymphoblastic leukemias indicated that 87.5% of the leukemias obtained from children < or = 3 yr old lacked N regions at the DJH junction. In contrast, in children > 3 yr old, only 11.1% of the leukemias lacked N regions at this junction, a frequency similar to what we have observed in B cells from children and adults. These findings suggest that the majority of leukemias presenting within the first 3 yr of age arise from an in utero transforming event.

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Selected References

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  1. Allansmith M., McClellan B. H., Butterworth M., Maloney J. R. The development of immunoglobulin levels in man. J Pediatr. 1968 Feb;72(2):276–290. doi: 10.1016/s0022-3476(68)80324-5. [DOI] [PubMed] [Google Scholar]
  2. Bangs L. A., Sanz I. E., Teale J. M. Comparison of D, JH, and junctional diversity in the fetal, adult, and aged B cell repertoires. J Immunol. 1991 Mar 15;146(6):1996–2004. [PubMed] [Google Scholar]
  3. Blackwell T. K., Alt F. W. Molecular characterization of the lymphoid V(D)J recombination activity. J Biol Chem. 1989 Jun 25;264(18):10327–10330. [PubMed] [Google Scholar]
  4. Feeney A. J. Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences. J Exp Med. 1990 Nov 1;172(5):1377–1390. doi: 10.1084/jem.172.5.1377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Foon K. A., Todd R. F., 3rd Immunologic classification of leukemia and lymphoma. Blood. 1986 Jul;68(1):1–31. [PubMed] [Google Scholar]
  6. Greaves M. F. Differentiation-linked leukemogenesis in lymphocytes. Science. 1986 Nov 7;234(4777):697–704. doi: 10.1126/science.3535067. [DOI] [PubMed] [Google Scholar]
  7. Greaves M. F. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia. 1988 Feb;2(2):120–125. [PubMed] [Google Scholar]
  8. Gregoire K. E., Goldschneider I., Barton R. W., Bollum F. J. Ontogeny of terminal deoxynucleotidyl transferase-positive cells in lymphohemopoietic tissues of rat and mouse. J Immunol. 1979 Sep;123(3):1347–1352. [PubMed] [Google Scholar]
  9. Gu H., Förster I., Rajewsky K. Sequence homologies, N sequence insertion and JH gene utilization in VHDJH joining: implications for the joining mechanism and the ontogenetic timing of Ly1 B cell and B-CLL progenitor generation. EMBO J. 1990 Jul;9(7):2133–2140. doi: 10.1002/j.1460-2075.1990.tb07382.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kallenbach S., Doyen N., Fanton d'Andon M., Rougeon F. Three lymphoid-specific factors account for all junctional diversity characteristic of somatic assembly of T-cell receptor and immunoglobulin genes. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2799–2803. doi: 10.1073/pnas.89.7.2799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Korsmeyer S. J., Arnold A., Bakhshi A., Ravetch J. V., Siebenlist U., Hieter P. A., Sharrow S. O., LeBien T. W., Kersey J. H., Poplack D. G. Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T cell and B cell precursor origins. J Clin Invest. 1983 Feb;71(2):301–313. doi: 10.1172/JCI110770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lafaille J. J., DeCloux A., Bonneville M., Takagaki Y., Tonegawa S. Junctional sequences of T cell receptor gamma delta genes: implications for gamma delta T cell lineages and for a novel intermediate of V-(D)-J joining. Cell. 1989 Dec 1;59(5):859–870. doi: 10.1016/0092-8674(89)90609-0. [DOI] [PubMed] [Google Scholar]
  13. Lewis S., Gellert M. The mechanism of antigen receptor gene assembly. Cell. 1989 Nov 17;59(4):585–588. doi: 10.1016/0092-8674(89)90002-0. [DOI] [PubMed] [Google Scholar]
  14. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  15. Nadler L. M., Korsmeyer S. J., Anderson K. C., Boyd A. W., Slaughenhoupt B., Park E., Jensen J., Coral F., Mayer R. J., Sallan S. E. B cell origin of non-T cell acute lymphoblastic leukemia. A model for discrete stages of neoplastic and normal pre-B cell differentiation. J Clin Invest. 1984 Aug;74(2):332–340. doi: 10.1172/JCI111428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Oettinger M. A., Schatz D. G., Gorka C., Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. doi: 10.1126/science.2360047. [DOI] [PubMed] [Google Scholar]
  17. Pascual V., Capra J. D. Human immunoglobulin heavy-chain variable region genes: organization, polymorphism, and expression. Adv Immunol. 1991;49:1–74. doi: 10.1016/s0065-2776(08)60774-9. [DOI] [PubMed] [Google Scholar]
  18. Rothenberg E., Triglia D. Clonal proliferation unlinked to terminal deoxynucleotidyl transferase synthesis in thymocytes of young mice. J Immunol. 1983 Apr;130(4):1627–1633. [PubMed] [Google Scholar]
  19. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  20. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sanz I. Multiple mechanisms participate in the generation of diversity of human H chain CDR3 regions. J Immunol. 1991 Sep 1;147(5):1720–1729. [PubMed] [Google Scholar]
  22. Schatz D. G., Oettinger M. A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. doi: 10.1016/0092-8674(89)90760-5. [DOI] [PubMed] [Google Scholar]
  23. Schroeder H. W., Jr, Wang J. Y. Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6146–6150. doi: 10.1073/pnas.87.16.6146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  25. Wasserman R., Ito Y., Galili N., Yamada M., Reichard B. A., Shane S., Lange B., Rovera G. The pattern of joining (JH) gene usage in the human IgH chain is established predominantly at the B precursor cell stage. J Immunol. 1992 Jul 15;149(2):511–516. [PubMed] [Google Scholar]
  26. Wasserman R., Yamada M., Ito Y., Finger L. R., Reichard B. A., Shane S., Lange B., Rovera G. VH gene rearrangement events can modify the immunoglobulin heavy chain during progression of B-lineage acute lymphoblastic leukemia. Blood. 1992 Jan 1;79(1):223–228. [PubMed] [Google Scholar]
  27. Yamada M., Hudson S., Tournay O., Bittenbender S., Shane S. S., Lange B., Tsujimoto Y., Caton A. J., Rovera G. Detection of minimal disease in hematopoietic malignancies of the B-cell lineage by using third-complementarity-determining region (CDR-III)-specific probes. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5123–5127. doi: 10.1073/pnas.86.13.5123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Yamada M., Wasserman R., Lange B., Reichard B. A., Womer R. B., Rovera G. Minimal residual disease in childhood B-lineage lymphoblastic leukemia. Persistence of leukemic cells during the first 18 months of treatment. N Engl J Med. 1990 Aug 16;323(7):448–455. doi: 10.1056/NEJM199008163230705. [DOI] [PubMed] [Google Scholar]
  29. Yamada M., Wasserman R., Reichard B. A., Shane S., Caton A. J., Rovera G. Preferential utilization of specific immunoglobulin heavy chain diversity and joining segments in adult human peripheral blood B lymphocytes. J Exp Med. 1991 Feb 1;173(2):395–407. doi: 10.1084/jem.173.2.395. [DOI] [PMC free article] [PubMed] [Google Scholar]

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