Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22

We have identified and molecularly cloned 46 kb of human DNA from chromosome 22 using a probe specific for the Philadelphia (Ph') translocation breakpoint domain of one chronic myelocytic leukemia (CML) patient. The DNAs of 19 CML patients were examined for rearrangements on chromosome 22 with probes isolated from this cloned region. In 17 patients, chromosomal breakpoints were found within a limited region of up to 5.8 kb, for which we propose the term "breakpoint cluster region" (bcr). The two patients having no rearrangements within bcr lacked the Ph' chromosome. The highly specific presence of a chromosomal breakpoint within bcr in Ph'-positive CML patients strongly suggests the involvement of bcr in this type of leukemia.

[1]  A. Jeffreys,et al.  A physical map of the DNA regions flanking the rabbit β-globin gene , 1977, Cell.

[2]  J. Stephenson,et al.  The human v-abl cellular homologue. , 1983, Journal of molecular and applied genetics.

[3]  E. Gelmann,et al.  A human onc gene homologous to the transforming gene (v-sis) of simian sarcoma virus , 1981, Nature.

[4]  J. Stephenson,et al.  Isolation of human oncogene sequences (v-fes homolog) from a cosmid library. , 1982, Science.

[5]  C. Croce,et al.  Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. , 1983, Science.

[6]  J. Stephenson,et al.  Regulation of viral and cellular oncogene expression by cytosine methylation. , 1983, Virology.

[7]  T. Rabbitts,et al.  Translocation joins c-myc and immunoglobulin γ1 genes in a Burkitt lymphoma revealing a third exon in the c-myc oncogene , 1983, Nature.

[8]  J. Stephenson,et al.  A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia , 1982, Nature.

[9]  J. Rowley,et al.  Identification of the constant chromosome regions involved in human hematologic malignant disease. , 1982, Science.

[10]  U. Storb,et al.  Physical linkage of the constant region genes for immunoglobulins lambda I and lambda III. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. de la Chapelle,et al.  Lambda Ig constant region genes are translocated to chromosome 8 in Burkitt's lymphoma with t(8;22). , 1983, Nucleic acids research.

[12]  J. Stephenson,et al.  Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia , 1983, Nature.

[13]  R. Flavell,et al.  Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH). , 1980, Nucleic acids research.

[14]  A. Hagemeijer,et al.  Clonal origin of the Philadelphia translocation in chronic myeloid leukemia demonstrated in somatic cell hybrids using an adenylate kinase-1 polymorphism. , 1982, Cancer genetics and cytogenetics.

[15]  A. Hagemeijer,et al.  Localization of the human c-sis oncogene in Ph1-positive and Ph1- negative chronic myelocytic leukemia by in situ hybridization , 1984 .

[16]  D. Baltimore,et al.  Structure of the Abelson murine leukemia virus genome and the homologous cellular gene: Studies with cloned viral DNA , 1980, Cell.

[17]  S. Cory,et al.  Cellular myc oncogene is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[18]  P. Leder,et al.  Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[19]  C. Croce,et al.  Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[20]  A. Hagemeijer,et al.  Characterization of the Philadelphia chromosome by gene mapping. , 1981, Cytogenetics and cell genetics.

[21]  J. Stephenson,et al.  Localization of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukaemia , 1983, Nature.

[22]  E. Gelmann,et al.  Expression of cellular homologues of retroviral onc genes in human hematopoietic cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[23]  E. Southern.  Detection of specific sequences among DNA fragments separated by gel electrophoresis. , 1975, Journal of molecular biology.

[24]  J. Stephenson,et al.  c-sis is translocated from chromosome 22 to chromosome 9 in chronic myelocytic leukemia , 1983, The Journal of experimental medicine.

[25]  P. Nowell,et al.  Translocation of immunoglobulin VH genes in Burkitt lymphoma. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Rowley.  A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining , 1973, Nature.

[27]  J Erikson,et al.  Transcriptional activation of the translocated c-myc oncogene in burkitt lymphoma. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Goodfellow,et al.  Chromosomal localization of human cellular homologues of two viral oncogenes , 1982, Nature.

[29]  F. Grosveld,et al.  Isolation of β-globin related genes from a human cosmid library. , 1981 .

[30]  J. Yunis.  The chromosomal basis of human neoplasia. , 1983, Science.

[31]  P. Leder,et al.  Chromosomal location of human kappa and lambda immunoglobulin light chain constant region genes , 1982, The Journal of experimental medicine.

[32]  A. Hagemeijer,et al.  Decreased tumorigenicity of rodent cells after fusion with leukocytes from normal and leukemic donors , 1981, Somatic cell genetics.

[33]  B. Ozanne,et al.  Transforming gene of a human leukaemia cell is unrelated to the expressed tumour virus related gene of the cell , 1982, Nature.

[34]  R. Williamson,et al.  Analysis of the β-δ-globin gene loci in normal and hb lepore DNA: Direct determination of gene linkage and intergene distance , 1978, Cell.