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Myelogenous Leukemia 8;21 Translocation: Evidence That C-Mos Is Not Translocated [Somatic Cell Hybrids/C-Myc/Gene Mapping/Superoxide Dismutase (Soluble)] HARRY A

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Myelogenous Leukemia 8;21 Translocation: Evidence That C-Mos Is Not Translocated [Somatic Cell Hybrids/C-Myc/Gene Mapping/Superoxide Dismutase (Soluble)] HARRY A Proc. Natl. Acad. Sci. USA Vol. 82, pp. 464-468, January 1985 Genetics Isolation and analysis of the 21q+ chromosome in the acute myelogenous leukemia 8;21 translocation: Evidence that c-mos is not translocated [somatic cell hybrids/c-myc/gene mapping/superoxide dismutase (soluble)] HARRY A. DRABKIN*t, MANUEL DIAZt, CYNTHIA M. BRADLEY*, MICHELLE M. LE BEAUS, JANET D. ROWLEYt, AND DAVID PATTERSON*§¶ *The Eleanor Roosevelt Institute for Cancer Research, 4200 East Ninth Avenue, B-129, and tThe Division of Medical Oncology and Departments of Medicine and ¶Biochemistry, Biophysics and Genetics, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262; and tSection of Hematology-Oncology, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637 Contributed by Janet D. Rowley, September 4, 1984 ABSTRACT Acute myelogenous leukemia (AML), sub- light chain genes are translocated to the 3' region of c-myc group M2, is associated with a nonrandom chromosomal (4-7). translocation, t(8;21)(q22,q22). The oncogene c-mos also has Somatic cell genetic approaches have been used also to been localized to the q22 band on chromosome 8. There is also show that, in Philadelphia (Ph')-positive chronic myeloge- evidence that genes on chromosome 21 may be important in nous leukemia, c-abl oncogene sequences are translocated the development of leukemia. To determine whether the c-mos from chromosome 9 to the Ph' (22q-) chromosome (8). oncogene has been translocated in AML-M2 with this translo- Analysis of cells from two Ph'-positive patients has revealed cation and to isolate DNA sequences and genes from these two that the breakpoint in chromosome 9 is near c-abl (9). Again, chromosomes that may be important in malignancy, we con- the exact breakpoints have proven to be somewhat heteroge- structed somatic cell hybrids between a Chinese hamster ovary neous, although there is good evidence for clustering of the cell (CHO) mutant defective in glycine metabolism and myelo- breakpoints on chromosome 22 in various patients. blasts with an 8;21 translocation from a patient with AML. We A nonrandom chromosome translocation, t(8;21)- isolated the 21q+ chromosome of this translocation in a somat- (q22;q22), which results in an 8q- and 21q+ chromosome, is ic cell hybrid and showed that the c-mos oncogene had not seen almost exclusively in the M2 subtype of acute myelo- been translocated to chromosome 21, ruling out the possibility blastic leukemia (AML with maturation). Eighteen percent that translocation of c-mos to chromosome 21 is necessary for of all patients with AML and the M2 morphology have been development of AML-M2. In addition, there was no detectable found to have a 8;21 translocation [t(8;21)] (10). The c-mos rearrangement of the c-mos locus within a 12.4-kilobase region oncogene, which has been assigned to chromosome 8 by so- surrounding the gene, indicating that rearrangement of the matic cell genetic techniques (11), has been mapped by using coding region of the gene itself or alteration of proximal 5' or in situ hybridization to band 8q22, the band involved in the 3' flanking sequences is not involved. We used this hybrid to 8;21 translocation (12). Moreover, band 21q22, the site of the determine whether specific DNA sequences and biochemical breakpoint on the chromosome 21 involved in this transloca- markers from chromosomes 8 and 21 had been translocated in tion, is a region which, when trisomic, leads to the develop- this case. ment of Down syndrome, the most common chromosomal cause of mental retardation in humans and a chromosomal The discovery of nonrandom chromosomal abnormalities as- disease with an increased risk of leukemia (13). Thus, there sociated with various types of malignant diseases has gener- may be genes on chromosome 21 whose abnormal regulation ated considerable impetus for the isolation and characteriza- may be significant in leukemia. tion of the abnormal chromosomes and for the determination To determine what genes and DNA sequences are associ- of the nature of the DNA sequences and genes located at or ated with the 8;21 translocation in AML and, in particular, to near the site of chromosomal rearrangement. The specificity determine whether translocation of c-mos to chromosome 21 of these rearrangements suggests a relationship between the is required for development of AML, we isolated from a pa- chromosomal abnormalities and the development of specific tient with this disease somatic cell hybrids that contain the malignant diseases (1). Recently, this relationship has been 21q+ portion of this chromosomal rearrangement. Analysis extended to the molecular level by a combination of somatic of these hybrids indicates that, at least in this patient, the c- cell genetic and molecular approaches. Thus, the c-myc on- mos oncogene is not translocated to the 21q+ chromosome cogene normally located on chromosome 8 is translocated to and that no rearrangements can be detected in an area of 12.4 chromosome 14 in the region of the immunoglobulin heavy kb around this gene. Thus, neither translocation of c-mos to chain locus in Burkitt lymphoma with an 8;14 translocation chromosome 21 nor gross rearrangement of the gene is nec- (2, 3). In some cases, the c-myc gene is rearranged, the essary for the occurrence of AML-M2 with the 8;21 translo- breakpoint on chromosome 8 being located in the first intron cation. of the gene, while in other cases, the c-myc gene is not re- arranged, the junction being at least 50 kilobases (kb) from MATERIALS AND METHODS the gene. In relatively rare cases of Burkitt lymphoma in- Cells and Media. The Chinese hamster ovary (CHO) cell volving either a 2;8 or 8;22 translocation, the c-myc onco- parent, Gly-B, has a defect in glycine metabolism (14) that is gene remains on chromosome 8, and the immunoglobulin Abbreviations: AML, acute myelogenous leukemia; SODI, super- The publication costs of this article were defrayed in part by page charge oxide dismutase (soluble); CHO, Chinese hamster ovary; kb, kilo- payment. This article must therefore be hereby marked "advertisement" base(s); GSR, glutathione reductase; LDHA, lactose dehydrogenase in accordance with 18 U.S.C. §1734 solely to indicate this fact. A; HEXA, hexosaminidase A. 464 Downloaded by guest on September 24, 2021 Genetics: Drabkin et aL Proc. NatL Acad. Sci. USA 82 (1985) 465 complemented by human chromosome 8 (15). Gly-B cells XAR-5 film for various periods. were grown in F12 medium (16) supplemented with 6% (vol/ Molecular Probes. The human c-myc cDNA probe, pRyc- vol) fetal calf serum. 7.4 (27) and the immunoglobulin X heavy chain constant re- The patient was a 60-year-old man in second relapse, the gion gene (CA) probe (28), which contains the 8-kb EcoRI last chemotherapy having been given 3 months prior as con- Ke-Oz-/Ke-Oz+ fragment, were kindly provided by C. solidation therapy while still in remission. The complete Croce. The human mos probe used was a 2.7-kb EcoRI frag- karyotype of the leukemic cells was 45,X,-Y,t(8;21)- ment derived from XHM1 (29) kindly provided by G. Vande (q22;q22), del(9)(qll or ql2q31), which was seen in 97% of Woude. The human chromosome 21-specific probes CP2, the metaphase cells examined. The marrow cells were proc- CP8, and CP21G1 (18) were kindly provided by J. Davidson. essed by our usual methods (17). 706B6 clone 17 is a CHO-human hybrid containing chro- RESULTS mosome 8 as the only human material (15). 2FUrl and A Southern blot analysis of DNA from the patient's leuke- 72532X-6 are CHO-human hybrids containing the long arm mic bone marrow cells digested with either BamHI or BglII of chromosome 21 and the entire chromosome 21, respec- demonstrated only germ-line size fragments (data not tively, as their only cytogenetically detectable human mate- shown). This analysis covers a distance of 12.4 kb around rial (18). the c-mos gene and suggests that the breakpoint must be lo- Isolation of Somatic Cell Hybrids Between GlyfB and AML cated outside this region. Thus, alteration in 5' or 3' proxi- Cells Containing the 8;21 Translocation. Cell fusions between mal regulatory elements near c-mos or alterations in the cod- the Gly-B and AML cells were done by using UV-inactivat- ing sequence of this gene large enough to be detected by this ed Sendai virus as described (19). Cells (-1 x 106) from each Southern hybridization analysis are not required for devel- parent were used, and prior to fusions the leukemic cells opment of AML. were separated from mature erythrocytes and granulocytes Fusion of CHO Gly-B cells with cells from the bone mar- on a Ficoll/Hypaque gradient. Hybrids were selected by row ofthe patient resulted in 22 separate clones. Because the their growth in F12D medium (20) with 6% (vol/vol) dialyzed region of chromosome 8 that complements the Gly-B defect fetal calf serum that lacks glycine and does not support is 8q21.1-*qter (30), we initially screened 15 clones for the growth of the Gly-B parent. presence of the human GSR gene (GSR) which is located at Cytogenetic Analysis. To identify human chromosomes in 8p2l.1 (31). Four of the 15 clones were negative for human CHO-human hybrids, Giemsa/trypsin banding and Giemsa- GSR, suggesting that they might contain the 8;21 transloca- 11 staining were performed as described by Morse et al. (21) tion or other fragments of chromosome 8 that allowed and Alhadeff et al. (22). After Giemsa/trypsin banding, se- growth in deficient media.
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