Skip to main content
NCBI 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
. 1992 Jun 1;89(11):4923–4927. doi: 10.1073/pnas.89.11.4923

Molecular cloning of the breakpoints of a complex Philadelphia chromosome translocation: identification of a repeated region on chromosome 17.

T W McKeithan 1, L Warshawsky 1, R Espinosa 3rd 1, M M LeBeau 1
PMCID: PMC49200  PMID: 1594595

Abstract

Complex translocations in chronic myelogenous leukemia involve various chromosomes, in addition to chromosomes 9 and 22, in a nonrandom fashion. We have analyzed the DNA from leukemia cells characterized by a complex translocation, t(9;22;10;17)(q34;q11;p13;q21), by using the techniques of Southern blot hybridization, in situ hybridization, and molecular cloning; one of the breakpoints is at 17q21, a band that is frequently involved in complex 9;22 translocations. All of the breakpoint junctions and the corresponding normal sequences from the four involved chromosomes have been molecularly cloned. Restriction mapping is consistent with a simple concerted exchange of chromosomal material among the four chromosomes, except that additional changes appeared to have occurred within the chromosome 17 sequences. The cloned sequences on chromosome 17 at band q21 were found to be repeated in normal cells. By fluorescence in situ hybridization, a strong signal is seen at 17q21, but a weaker signal is also present at 17q23. By comparison with other primate species, an inversion in chromosome 17 during evolution appears to be responsible for the splitting of the cluster of repeat units in normal human cells.

Full text

PDF
4923

Images in this article

4924Image
on p.4924
4924Image
on p.4924
4925Image
on p.4925
4926Image
on p.4926

Selected References

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

  1. Bernstein R. Cytogenetics of chronic myelogenous leukemia. Semin Hematol. 1988 Jan;25(1):20–34. [PubMed] [Google Scholar]
  2. Daley G. Q., Van Etten R. A., Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824–830. doi: 10.1126/science.2406902. [DOI] [PubMed] [Google Scholar]
  3. De Braekeleer M. Variant Philadelphia translocations in chronic myeloid leukemia. Cytogenet Cell Genet. 1987;44(4):215–222. doi: 10.1159/000132374. [DOI] [PubMed] [Google Scholar]
  4. Dubé I., Dixon J., Beckett T., Grossman A., Weinstein M., Benn P., McKeithan T., Norman C., Pinkerton P. Location of breakpoints within the major breakpoint cluster region (bcr) in 33 patients with bcr rearrangement-positive chronic myeloid leukemia (CML) with complex or absent Philadelphia chromosomes. Genes Chromosomes Cancer. 1989 Sep;1(1):106–111. doi: 10.1002/gcc.2870010116. [DOI] [PubMed] [Google Scholar]
  5. Heim S., Billström R., Kristoffersson U., Mandahl N., Strömbeck B., Mitelman F. Variant Ph translocations in chronic myeloid leukemia. Cancer Genet Cytogenet. 1985 Nov;18(3):215–227. doi: 10.1016/0165-4608(85)90086-x. [DOI] [PubMed] [Google Scholar]
  6. Ishihara T., Minamihisamatsu M. The Philadelphia chromosome. Considerations based on studies of variant Ph translocations. Cancer Genet Cytogenet. 1988 May;32(1):75–92. doi: 10.1016/0165-4608(88)90314-7. [DOI] [PubMed] [Google Scholar]
  7. Konopka J. B., Watanabe S. M., Witte O. N. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell. 1984 Jul;37(3):1035–1042. doi: 10.1016/0092-8674(84)90438-0. [DOI] [PubMed] [Google Scholar]
  8. Lawrence J. B., Singer R. H., McNeil J. A. Interphase and metaphase resolution of different distances within the human dystrophin gene. Science. 1990 Aug 24;249(4971):928–932. doi: 10.1126/science.2203143. [DOI] [PubMed] [Google Scholar]
  9. Le Beau M. M., Westbrook C. A., Diaz M. O., Rowley J. D. Evidence for two distinct c-src loci on human chromosomes 1 and 20. Nature. 1984 Nov 1;312(5989):70–71. doi: 10.1038/312070a0. [DOI] [PubMed] [Google Scholar]
  10. Litt M., White R. L. A highly polymorphic locus in human DNA revealed by cosmid-derived probes. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6206–6210. doi: 10.1073/pnas.82.18.6206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. McKeithan T. W., Ohno H., Diaz M. O. Identification of a transcriptional unit adjacent to the breakpoint in the 14;19 translocation of chronic lymphocytic leukemia. Genes Chromosomes Cancer. 1990 Jan;1(3):247–255. doi: 10.1002/gcc.2870010310. [DOI] [PubMed] [Google Scholar]
  12. McLaughlin J., Chianese E., Witte O. N. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6558–6562. doi: 10.1073/pnas.84.18.6558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Miró R., Clemente I. C., Fuster C., Egozcue J. Fragile sites, chromosome evolution, and human neoplasia. Hum Genet. 1987 Apr;75(4):345–349. doi: 10.1007/BF00284105. [DOI] [PubMed] [Google Scholar]
  14. Morris C., Kennedy M., Heisterkamp N., Columbano-Green L., Romeril K., Groffen J., Fitzgerald P. A complex chromosome rearrangement forms the BCR-ABL fusion gene in leukemic cells with a normal karyotype. Genes Chromosomes Cancer. 1991 Jul;3(4):263–271. doi: 10.1002/gcc.2870030405. [DOI] [PubMed] [Google Scholar]
  15. Murnane J. P., Young B. R. Nucleotide sequence analysis of novel junctions near an unstable integrated plasmid in human cells. Gene. 1989 Dec 7;84(1):201–205. doi: 10.1016/0378-1119(89)90157-1. [DOI] [PubMed] [Google Scholar]
  16. Rowley J. D., Diaz M. O., Espinosa R., 3rd, Patel Y. D., van Melle E., Ziemin S., Taillon-Miller P., Lichter P., Evans G. A., Kersey J. H. Mapping chromosome band 11q23 in human acute leukemia with biotinylated probes: identification of 11q23 translocation breakpoints with a yeast artificial chromosome. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9358–9362. doi: 10.1073/pnas.87.23.9358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rowley J. D., Testa J. R. Chromosome abnormalities in malignant hematologic diseases. Adv Cancer Res. 1982;36:103–148. doi: 10.1016/s0065-230x(08)60423-6. [DOI] [PubMed] [Google Scholar]
  18. Smeets D. F., van de Klundert F. A. Common fragile sites in man and three closely related primate species. Cytogenet Cell Genet. 1990;53(1):8–14. doi: 10.1159/000132885. [DOI] [PubMed] [Google Scholar]
  19. Stam K., Heisterkamp N., Grosveld G., de Klein A., Verma R. S., Coleman M., Dosik H., Groffen J. Evidence of a new chimeric bcr/c-abl mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. N Engl J Med. 1985 Dec 5;313(23):1429–1433. doi: 10.1056/NEJM198512053132301. [DOI] [PubMed] [Google Scholar]
  20. Trask B. J., Massa H., Kenwrick S., Gitschier J. Mapping of human chromosome Xq28 by two-color fluorescence in situ hybridization of DNA sequences to interphase cell nuclei. Am J Hum Genet. 1991 Jan;48(1):1–15. [PMC free article] [PubMed] [Google Scholar]
  21. Yunis J. J., Prakash O. The origin of man: a chromosomal pictorial legacy. Science. 1982 Mar 19;215(4539):1525–1530. doi: 10.1126/science.7063861. [DOI] [PubMed] [Google Scholar]
  22. Yunis J. J., Soreng A. L., Bowe A. E. Fragile sites are targets of diverse mutagens and carcinogens. Oncogene. 1987 Mar;1(1):59–69. [PubMed] [Google Scholar]
  23. de Klein A., van Agthoven T., Groffen C., Heisterkamp N., Groffen J., Grosveld G. Molecular analysis of both translocation products of a Philadelphia-positive CML patient. Nucleic Acids Res. 1986 Sep 11;14(17):7071–7082. doi: 10.1093/nar/14.17.7071. [DOI] [PMC free article] [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