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[CANCER RESEARCH 51. 3821-3824. July 15, 1991) Advances in Brief Chromosome Locations of the MYB Related Genes, AMYB and BMYB1 Cosimo Barletta, Teresa Druck, Sal LaForgia, Bruno Calabretta, Harry Drabkin, David Patterson, Carlo M. Croce, and Kay Huebner2 Raggio ¡talgene,Pomezia, Italy [C. B.]; Fels Institute for Cancer Research and Molecular Biology; Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [T. D., S. L., B. C, C. M. C., K. H.]; and Eleanor Roosevelt Institute, Denver, Colorado 80206 ¡H.D., D. P.] Abstract The MYB related loci, AMYB and BMYB, were localized to specific human chromosome regions by Southern blot analysis of their segregation patterns in a panel of rodent-human hybrid DNAs using radiolabeled AMYB and BMYB probes. The AMYB locus was present in hybrids retaining the chromosome region Seen—»8q22 and was absent in hybrids which had lost this chromosome region. The presence of the BMYB locus in rodent-human hybrids correlated with, and only with, chromo some region Xql3. Chromosomal in situ hybridization refined the local ization of AMYB to region 8q22-23 and confirmed the localization of BMYB to region Xql3. Chromosome region 8q22 is involved in recurrent translocations in malignant lymphoma and in acute myeloid leukemia (AML-M2); therefore AMYB is a candidate for involvement in such translocations. A region on Xql3 is also involved in chromosomal abnor malities in acute myeloid leukemia and myelodysplasias. Introduction The MYB protooncogene is an evolutionarily conserved cel lular gene first identified by its homology to the transforming gene, \-myb, of avian myeloblastosis and erythroblastosis vi ruses (for review, see Ref. l ). The protein encoded by the MYB gene is a nuclear protein (2) reportedly expressed predomi nantly in normal and neoplastic cells of hematopoietic origin (3). Early studies had indicated a role for MYB in differentiation (3-5) and recent evidence suggests that the MYB gene product is required for cell proliferation (6, 7). Nomura et al. (8) have isolated and characterized cDNA3 clones for two human MYB related genes, AMYB and BMYB, and expression of the MYB family of genes has been examined in a spectrum of neoplastic cell lines (8) and in normal hema topoietic cells (9). Neoplastic lymphoid cell lines expressed high levels of all three MYB family genes; BMYB was expressed in a wide spectrum of neoplastic cell types, including many of nonhematopoietic origin, while AMYB was expressed in a more restricted set of tumor types and at lower levels in the hematopoietic neoplastic cell lines tested (8). In normal T- and B-lymphocytes, MYB and BMYB mRNA was undetectable in resting cells and induced by mitogen stim ulation (9). AMYB, on the other hand, was expressed in resting T-lymphocytes and levels decreased after stimulation; AMYB was also expressed in a subpopulation of large B-lymphocytes but not in in vitro activated B-cells (9). In parallel with further studies on expression of MYB family Received 4/17/91; accepted 5/29/91. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by NIH Grants CA21124, CA39860. and HD17449. 2 To whom requests for reprints should be addressed, at Jefferson Cancer Institute, Thomas Jefferson University, 233 S. 10thSt.. Philadelphia. PA 191075541. 3 The abbreviations used are: cDNA. complementary DNA; SSC, standard saline-citrate (Ix SSC is 0.15 M NaCI-0.015 sodium citrate, pH 7.4). genes in the hematopoietic lineages and the effect of MYB family antisense oligonucleotides on hematopoietic colony for mation, we have determined the chromosomal locations of the new MYB family members, AMYB and BMYB. Materials and Methods Probes. The AMYB and BMYB cDNA probes (8) were obtained from Dr. Nobuo Nomura and colleagues of The Nippon Veterinary and Zootechnical College, Tokyo, Japan. The AMYB probe was a 602-base pair fragment from AMYB cDNA; the BMYB probe was a 1.4-kilobase £coRIfragment from a BMYB cDNA. Probes were nick translated with ("P]dCTP to a specific activity of 10" cpm/0.1 n% for filter hybridization. Cells. Isolation, propagation, and characterization of most parental and somatic cell hybrids used in this study have been described (10, 11). Hybrids GM9142, 7298, 7300, 7297, and 10095 were obtained from the National Institute for General Medical Sciences Human Genetic Mutant Cell Repository (Coriell Institute, Camden, NJ). Hy brid GM10095 carries a der(9)(9pter-»9q34::Xql3-»Xqter) (12) from a female carrying a balanced t(X;9)(ql3;q34). Other hybrids carrying partial chromosomes 8 or X have been described (13-17). Southern Blot Analysis. DNAs from human peripheral blood lym phocytes or human cell lines, mouse cell lines, and rodent-human hybrid cells were prepared by cell lysis, proteinase K digestion, phenol extrac tion, and ethanol precipitation. Cellular DNAs were digested with an excess of appropriate restriction enzymes, sized in 0.8% agarose gels, transferred to nylon filters (Duralon, Stratagene), and hybridized at 42°Cfor 16 h in 50% formamide, 5x saline-sodium phosphate-EDTA (the Ix concentration is 0.15 M NaCI-0.01 M NaH2PO.,-0.001 M EDTA, pH 7.4), 5x Denhardt's solution, 0.1% sodium dodecyl sulfate, and 100 Mg/ml salmon sperm DNA. Final washes of blots were in 0.1 x SSC-0.1% sodium dodecyl sulfate at 68°Cfor 1-3 h. Chromosomal in Situ Hybridization. AMYB and BMYB plasmids were labeled with 'H-labeled deoxynucleotide triphosphates by nick translation to a specific activity of 5 x IO7cpm/^ig. The preparation of chromosomes and in situ hybridization were performed according to established procedures (18, 19). After preliminary treatment of chro mosomes with pancreatic RNase A (1 h), denaturation of chromosomal DNA was performed in 70% formamide-2x SSC at 70°Cfor 2-5 min. Hybridization of slides was carried out in a mixture containing 50% formamide, 2x SSC, and 10% dextran sulfate at 37°Cfor 15 h. A 200fold excess of sonicated salmon sperm DNA was included as carrier. After hybridization, slides were rinsed once in a solution containing 50% formamide-2x SSC, pH 7.0, at room temperature and then in 2x SSC, pH 7.0, at 39°C,followed by dehydration in ethanol. For autoradiography, Kodak NTB2 emulsion was used at 4°Cfor 15 days. Finally, chromosomes were G-banded with Wright's stain and photographed. Results The AMYB Gene Localizes to Chromosome Region 8q22. More than 20 rodent-human hybrids were examined for the presence of the AMYB locus by hybridization of a radiolabeled human AMYB cDNA probe to EcoR\ cleaved hybrid and con trol DNAs immobilized on nylon filters. Results of testing of 3821 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1991 American Association for Cancer Research. CHROMOSOME LOCATIONS OF AMY B AND BMYB the entire panel demonstrated that theAMYB locus was present only in hybrids retaining chromosome 8 and was absent in all hybrids which did not contain chromosome 8, as summarized in Fig. 1. An example of such hybridization studies is shown in Fig. 2A. The AMYB cDNA probe detects three strongly hybrid izing human EcoR\ fragments (Fig. 2A, Lane /), two of which Human Chromosomes Fig. 1. Presence of AMYB and BMYB genes in a panel of 21 rodent-human hybrids. Stippled box indicates that the hybrid named in the left column contains the chromosome indicated in the upper row; box with lower stippling indicates presence of the long arm of the chromosome (or part of the long arm represented by a smaller fraction of stippling); hox with upper stippling indicates presence of the short arm (or partial short arm) of the chromosome; open box; the absence of the chromosome listed above the column. The columns for chromosomes 8 and X are boldly outlined and stippled to highlight correlation of the presence of these chromosomes (or regions of the chromosomes) with the presence of the AMYB and B.M YB genes, respectively. The pattern of retention of the A MYB and BMYB genes in the panel is shown to the right of the figure where presence of the gene in a hybrid is indicated by a stippled box with a plus sign and absence of the gene is indicated by an open box enclosing a minus sign. 123 are readily distinguishable from mouse AMYB fragments (Fig. 2A, Lane 9). The two diagnostic human AMYB fragments are present in hybrid DNA in lanes 2-4, 6, and 7 (Fig. 2A) which contain region Seen—»8q24 in common; AMYB negative hybrids contain no chromosome 8 (Fig. 2A, Lane 5) or contain region 8q24-^>8qter (Fig. 2A, Lane 8). Thus, the results summarized in Fig. 1 give a regional localization of AMYB to region Seen—» 8q24. In order to refine the regional localization, an additional pair of hybrids derived from leukemias carrying a t(8;21)(q22;q22) (15-17, 20) was tested. The 8q- hybrid DNA [retaining der 8(8pter—>8q22::21q22—>21qter]was negative for the AMYB locus while the 21q-l- DNA [der 21(21pter-^ 21q22::8q22—>8qter] was negative for the AMYB locus [not shown). The chromosome 8 sketch in Fig. 3 summarizes the regional mapping of the AMYB gene on chromosome 8. AMYB positive hybrids contain the region Seen—>8q22in common. In situ hybridization of the AMYB cDNA to normal human metaphase chromosomes showed a peak of hybridization to region 8q22—»8q23 (Fig. 4a) while rodent-human hybrid analy sis shows that AMYB is centromeric to an 8q22 translocation breakpoint. Thus, the AMYB gene is at 8q22. These results are in agreement with a preliminary finding by Nomura et al. (8), that the AMYB gene might be on chromosome 8. The BMYB Gene Maps to Xql3. The large panel of 21 EcoRl digested hybrid DNAs was also hybridized to a radiolabeled BMYB cDNA probe. Results are summarized in Fig. 1 and indicate linkage of the BMYB gene to a portion of the Xchromosome. An example of BMYB probe hybridization to hybrid DNAs is shown in Fig. 2B. EcoRl digested human DNA exhibits two strongly hybridizing fragments (Fig. IB, Lane 2) which are easily distinguishable from mouse BMYB fragments (Fig. 2B, Lane 1). Hybrids which retain Xq (Fig. 2B, Lane 6) or X (Lane 7) are positive for the human BMYB fragments while hybrids which do not retain X (Fig. IB, Lanes 3 and 5) or retain Xq24—>qter(Fig. IB, Lane 4) are negative for human BMYB fragments. 456789 1234567 kbp kbp 9.5 — 6.7 - -10 — 4.3 — ~4 — Fig. 2. Presence of AMYB and BMYB genes in rodent-human hybrids carrying partial chromosomes 8 and X. A, AMYB in hybrids carrying partial chromosome 8. DNA (~10 jig/lane) from human (Lane /). hybrid 5J retaining a der(8)(8pter—»8q24::3p21—>3pter)and other human chromosomes (missing normal 8 and region 8q24—>8qter)(Lane 2), J14-2 retaining partial I; partial 2. 3, 4; partial 5, 6. 7. Spter—8q24. 9-12, 14. 15. 17, 18, I9q, 21, 22 (Lane 3), hybrid 8cN retaining 4, 5q, 6q, 7. 8q, 12, 14, 17, partial 18, 21, 22 (Lane 4), hybrid 77-30 retaining partial Ip. 3, partial 4p. 5-7. 9. lOq. 13. 14. 17. 20-22, and X (Lane 5), hybrid 77-31N retaining 1. 3, partial 4p. 5-9. lOq. 13, 14, 17, 18, 20-22. and X (Lane 6). hybrid 16 retaining a der(8)(8pter—«8q24::22ql 1—»22qter) from a Burkitt's lymphoma and other human chromosomes (missing normal 8 and region 8q24—>8qter)(Ijtne 7). hybrid M44 retaining 8q24—>8qter.partial 12. partial 13. 14pter—»14q32 (Lane S), and mouse (Lane 9) was digested with restriction enzyme EcoRl, fractionated, transferred to a filter, and hybridized to the radiolabeled AMYB probe. Breakpoints of hybrids carrying partial or translocated chromosome 8 are described in the legend to Fig. 3. B, BMYB in hybrids carrying chromosome X or partial X. DNA (~10 /ig/lane) from mouse (Lane I), human (Lane 2), hybrid 8cN retaining chromosomes 4, 5q. 6q. 7. 8q, 12. 14, 17, partial 18. 21. and 22 (Lane 3), hybrid 734 retaining a der(l l)(l Ipter—1 lq23::.\q24-26->qter) and a partial 13 (Lane 4). hybrid 9142 retaining 3,5 and a der(21)(21qter-.21p21::Xp21-.Xpter) (Lane 5). hybrid 7298 retaining 4. 1Iq. 14. 20, 21. and Xq (Ijine 6). and hybrid 7300 retaining 6. 8. 11, and X (Lane 7) was digested with EcoRl. fractionated, transferred to filter, and hybridized to the radiolabeled BMYB probe. Note that hybrids in Lanes 6 and 7 are hamster-human hybrids and thus show hamster bands of higher molecular weight than the highest mouse band. The ~4-kilobase (kbp) human band is not seen in Lane 7 due to underloading of the DNA. Hybrids carrying partial X are further described in Fig. 3. 3822 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1991 American Association for Cancer Research. CHROMOSOME LOCATIONS OF AMYB AND BMYB AA3 9142 22.3 22.2 22.1 8q~ 5J 16 EF3d17 21.3 233 ¡ 23 1 t 7298 8c - 7-17 21.3 22.1 223 734 21qM44 AMYB BMYB - 21 il 21 2 L 21 3 I 22 1 [ 223 [ 8 Fig. 3. Regional localization of AMYB and BMYB genes. DNA from rodent-human hybrids retaining portions of chromosome 8 or X were tested for retention of the respective genes as described in Fig. 2. Most hybrids retaining partial chromosome 8 have been described (10, 13, IS, 20, 26, 27); full name for hybrid designated 16 is 1-23-16, 8c in 8cN. Hybrid 5J was derived from fusion of a cell carrying a t(3,8)(p21,q24) (28, 29) and carries a der(8)(8pter-»8q24::3p21-»3pter) in which the break on chromosome 8 is an unknown distance 5' of the MYC locus (29). From the segregation pattern in these hybrids, the AMYB gene maps centromeric to the 8q22 break of the t(8;21)(q22;q22). For chromosome X hybrids 734 (also called cll3), 7-17 (full name 52-63-7-17), MCP6, and AA3 have been described (10, 14). Hybrids GM7298, GM9142, and GM10095 carry, respectively, a t(X;ll)(Xqter—cen-.llqter), a der(21)(21qter-»21pl2::Xp21-»Xpter), and a der(9)(9pter-. 9q34::Xql3—»Xqter).Hybrids 7-17 and MCP6 also carry region Xql3-»Xqter; the relative positions of the Xql3 breaks in the three hybrids 10095, 7-17, and MCP6 are not known as indicated by dotted region. Since 10095 is positive for the BMYB locus while hybrids 7-17 and MCP6 are negative, the 10095 break within Xql3 must be more centromeric than the breaks in hybrids 7-17 and MCP6, and the BMYB locus must map to the region of Xql3 present in 10095 but absent in 7-17 and MCP6. the region of Xql3 present in 10095 but missing in the two hybrids 7-17 and MCP6, with the more distal (telomeric) breaks. In situ hybridization of the BMYB probe to human metaphase chromosomes showed a peak of grains over chromosome region Xql3 (see Fig. 4b). Thus the BMYB gene maps to chromosome region Xql3. i.. «P HP ...... ..-jl. _._._. |nrMim [••»••ii|iiii»i^iffy»n| ^S^^lflâ„¢?â„¢^ Discussion Because of its capture by retroviruses in chickens, its activa tion by proviral insertion in murine tumors (21-23), and its pivotal role in hematopoietic cell proliferation, evidence for • •• inumi m rearrangement of the MYB gene in human hematopoietic neo plasms has been sought. Although the MYB locus maps to chromosome region 6q22-23 (individual references cited in !• • II •M» !!•!••Ill Mill ¡••••II mm Ml ••!•!! Ref. 24), a region dense with neoplasia associated chromosomal abnormalities, especially deletions, sighted in tumors of various •• • • * •••*lt*#«S •• (individual references cited in Ref. 25), the search for TTnoann^ci^ lineages direct involvement of the MYB gene in chromosomal re M 21 22 arrangements in human neoplasias has not been notably Fig. 4. Localization of AMYB and BMYB genes by chromosomal in situ successful. hybridization. Normal human peripheral blood lymphocyte metaphases were examined by in situ hybridization using AMYB and BMYB cDNA probes, a, Thus, it seemed important to determine if other members of idiogram of grain distribution after in situ hybridization with radiolabeled AMYB the MYB gene family map to chromosome regions indicating probe. For the AMYB probe a total of 100 grains were counted on 75 metaphases, direct involvement in neoplasia specific chromosome abnor and 20 were located on chromosome 8. Most of these grains were clustered around the region 8q22. b, idiogram of grain distribution after in situ hybridization malities. The mapping of AMYB and BMYB genes to chro with radiolabeled BMYB probe. For the BMYB probe a total of 98 grains were mosome regions 8q22 and Xql3 is the first step in this counted on 80 metaphases, and 21 were located on chromosome X (with a cluster of grains on the region Xql3). The x2 calculated for the grain distributions on direction. both chromosomes 8 and X correspond to P < 0.0005. The analysis tests the Both chromosome regions 8q22 and Xql3 are involved in hypothesis that labeling is random over all chromosomes. characteristic chromosomal abnormalities in myeloid neoplasia or preneoplasia. The two genes are highly expressed in the Thus, the summary in Fig. 1 indicates that the BMYB gene hematopoietic lineage (8, 9). AMYB and BMYB loci are thus maps to Xcen—»Xq24. To narrow the localization further, three candidates for involvement in the respective chromosomal hybrids carrying the region Xq 13—»Xqter were also tested for translocations. presence of the BMYB gene. Results are summarized beside the sketch of the X-chromosome in Fig. 3. Hybrids 7-17 and MCP6 References (14) are negative for the BMYB locus while 10095 is positive. 1. Reddy, E. P. In: E. P. Reddy, A. M. Skalka, and T. Curran (eds.). The Since all three of these hybrids carry region Xq 13—»Xqter, the Oncogene Handbook, pp. 327-340. Amsterdam: Elsevier/North-Holland 10095 hybrid must have the more centromeric break as indi Biomedicai Press, 1988. 2. Klempnauer, K-H., Symonds, G., Evan, G. I., and Bishop, J. M. Subcellular cated in the drawing (Fig. 3) and the BMYB gene must map to 7 « s 1 9 ' 10 T 11 > 12 ... 3823 Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1991 American Association for Cancer Research. CHROMOSOME 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 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