0 11 Concomitant concomitant JJ 12 26 downregulation downregulation NN 27 29 of of IN 30 33 IgH IgH NNP 34 35 3 3 CD 35 36 ’ ' SYM 37 45 enhancer enhancer NN 46 54 activity activity NN 55 58 and and CC 59 64 c-myc c-myc NN 65 75 expression expression NN 76 78 in in IN 79 80 a a DT 81 93 plasmacytoma plasmacytoma NN 94 95 x x NN 96 106 fibroblast fibroblast NN 107 118 environment environment NN 118 119 : : : 120 132 implications implication NNS 133 136 for for IN 137 150 dysregulation dysregulation NN 151 153 of of IN 154 166 translocated translocate VBN 167 172 c-myc c-myc NN 172 173 . . . 175 185 Regulation regulation NN 186 188 of of IN 189 203 immunoglobulin immunoglobulin NN 204 209 heavy heavy JJ 210 215 chain chain NN 216 217 ( ( ( 217 220 IgH IgH NNP 220 221 ) ) ) 222 226 gene gene NN 227 237 expression expression NN 238 240 is be VBZ 241 251 controlled control VBN 252 254 by by IN 255 256 a a DT 257 258 B B NNP 259 272 cell-specific cell-specific JJ 273 281 promoter promoter NN 281 282 , , , 283 291 intronic intronic JJ 292 300 enhancer enhancer NN 301 304 and and CC 305 315 additional additional JJ 316 317 B B NNP 318 331 cell-specific cell-specific JJ 332 340 enhancer enhancer NN 341 349 elements element NNS 350 360 identified identify VBN 361 369 recently recently RB 370 372 in in IN 373 376 the the DT 377 378 3 3 CD 378 379 ’ ' SYM 380 383 end end NN 384 386 of of IN 387 390 the the DT 391 394 IgH IgH NNP 395 400 locus locus NN 400 401 . . . 402 405 One one CD 406 408 of of IN 409 412 the the DT 413 419 latter latter JJ 420 428 elements element NNS 428 429 , , , 430 433 the the DT 434 437 IgH IgH NNP 438 439 3 3 CD 439 440 ’ ' SYM 441 449 enhancer enhancer NN 449 450 , , , 451 453 is be VBZ 454 456 of of IN 457 467 particular particular JJ 468 476 interest interest NN 476 477 : : : 478 479 ( ( ( 479 480 1 1 LS 480 481 ) ) ) 482 484 it it PRP 485 487 is be VBZ 488 489 B B NNP 490 503 cell-specific cell-specific JJ 504 507 and and CC 508 514 active active JJ 515 519 only only RB 520 522 in in IN 523 527 late late JJ 528 529 B B NNP 530 534 cell cell NN 535 546 development development NN 546 547 ; ; : 548 549 ( ( ( 549 550 2 2 LS 550 551 ) ) ) 552 554 in in IN 555 561 rodent rodent JJ 562 575 plasmacytomas plasmacytoma NNS 576 579 and and CC 580 582 in in IN 583 587 some some DT 588 593 human human JJ 594 601 Burkitt Burkitt NNP 601 603 ’s 's POS 604 613 lymphomas lymphoma NNS 614 616 it it PRP 617 619 is be VBZ 620 624 part part NN 625 627 of of IN 628 629 a a DT 630 635 locus locus NN 636 643 control control NN 644 650 region region NN 651 652 ( ( ( 652 655 LCR LCR NNP 655 656 ) ) ) 657 661 that that WDT 662 664 is be VBZ 665 673 involved involve VBN 674 676 in in IN 677 689 deregulation deregulation NN 690 692 of of IN 693 696 the the DT 697 702 c-myc c-myc NN 703 711 oncogene oncogene NN 712 714 as as IN 715 716 a a DT 717 723 result result NN 724 726 of of IN 727 740 translocation translocation NN 741 745 into into IN 746 749 the the DT 750 753 IgH IgH NNP 754 759 locus locus NN 759 760 ; ; : 761 764 and and CC 765 766 ( ( ( 766 767 3 3 LS 767 768 ) ) ) 769 771 it it PRP 772 775 has have VBZ 776 780 been be VBN 781 791 implicated implicate VBN 792 794 in in IN 795 798 the the DT 799 809 mechanisms mechanism NNS 810 814 that that WDT 815 822 control control VBP 823 825 Ig ig NN 826 830 gene gene NN 831 836 class class NN 837 843 switch switch NN 844 857 recombination recombination NN 857 858 . . . 859 861 We we PRP 862 866 have have VBP 867 871 used use VBN 872 873 a a DT 874 881 somatic somatic JJ 882 886 cell cell NN 887 900 hybridization hybridization NN 901 909 approach approach NN 910 912 to to TO 913 924 genetically genetically RB 925 932 analyse analyse VB 933 943 regulation regulation NN 944 946 of of IN 947 950 the the DT 951 959 activity activity NN 960 962 of of IN 963 966 the the DT 967 970 IgH IgH NNP 971 972 3 3 CD 972 973 ’ ' SYM 974 982 enhancer enhancer NN 982 983 . . . 984 988 When when WRB 989 994 mouse mouse NN 995 1000 MPC11 mpc11 NN 1001 1013 plasmacytoma plasmacytoma NN 1014 1019 cells cell NNS 1019 1020 , , , 1021 1023 in in IN 1024 1029 which which WDT 1030 1033 the the DT 1034 1037 IgH IgH NNP 1038 1039 3 3 CD 1039 1040 ’ ' SYM 1041 1049 enhancer enhancer NN 1050 1052 is be VBZ 1053 1059 active active JJ 1059 1060 , , , 1061 1064 are be VBP 1065 1070 fused fuse VBN 1071 1075 with with IN 1076 1087 fibroblasts fibroblast NNS 1087 1088 , , , 1089 1091 Ig ig NN 1092 1102 expression expression NN 1103 1105 is be VBZ 1106 1118 extinguished extinguish VBN 1119 1121 at at IN 1122 1125 the the DT 1126 1131 level level NN 1132 1134 of of IN 1135 1148 transcription transcription NN 1148 1149 . . . 1150 1154 Here here RB 1155 1157 we we PRP 1158 1162 show show VBP 1163 1167 that that IN 1168 1170 in in IN 1171 1172 a a DT 1173 1178 MPC11 mpc11 NN 1179 1191 plasmacytoma plasmacytoma NN 1192 1193 x x NN 1194 1204 fibroblast fibroblast NN 1205 1216 environment environment NN 1216 1217 , , , 1218 1221 the the DT 1222 1225 IgH IgH NNP 1226 1227 3 3 CD 1227 1228 ’ ' SYM 1229 1237 enhancer enhancer NN 1238 1240 is be VBZ 1241 1258 transcriptionally transcriptionally RB 1259 1267 inactive inactive JJ 1267 1268 . . . 1269 1280 Furthermore furthermore RB 1280 1281 , , , 1282 1284 we we PRP 1285 1296 demonstrate demonstrate VBP 1297 1301 that that IN 1302 1309 binding binding NN 1310 1312 of of IN 1313 1320 several several JJ 1321 1322 B B NNP 1323 1336 cell-specific cell-specific JJ 1337 1350 transcription transcription NN 1351 1358 factors factor NNS 1358 1359 , , , 1360 1369 essential essential JJ 1370 1373 for for IN 1374 1377 IgH IgH NNP 1378 1379 3 3 CD 1379 1380 ’ ' SYM 1381 1389 enhancer enhancer NN 1390 1398 activity activity NN 1398 1399 , , , 1400 1402 is be VBZ 1403 1410 lacking lack VBG 1410 1411 , , , 1412 1417 which which WDT 1418 1421 may may MD 1422 1429 explain explain VB 1430 1431 3 3 CD 1431 1432 ’ ' SYM 1433 1441 enhancer enhancer NN 1442 1452 inactivity inactivity NN 1452 1453 , , , 1454 1462 although although IN 1463 1466 the the DT 1467 1474 binding binding NN 1475 1477 of of IN 1478 1488 repressors repressor NNS 1489 1495 cannot cannot MD 1496 1498 be be VB 1499 1507 excluded exclude VBN 1507 1508 . . . 1509 1517 Moreover moreover RB 1517 1518 , , , 1519 1522 the the DT 1523 1527 high high JJ 1528 1538 expression expression NN 1539 1544 level level NN 1545 1547 of of IN 1548 1553 c-myc c-myc NN 1553 1554 , , , 1555 1569 characteristic characteristic JJ 1570 1572 of of IN 1573 1576 the the DT 1577 1585 parental parental JJ 1586 1591 MPC11 mpc11 NN 1592 1597 cells cell NNS 1598 1606 carrying carry VBG 1607 1610 the the DT 1611 1619 t(12;15) t(12;15) NN 1620 1633 translocation translocation NN 1633 1634 , , , 1635 1637 is be VBZ 1638 1652 down-regulated down-regulate VBN 1653 1655 in in IN 1656 1659 the the DT 1660 1667 hybrids hybrid NNS 1668 1670 to to TO 1671 1675 that that DT 1676 1678 in in IN 1679 1686 unfused unfused JJ 1687 1698 fibroblasts fibroblast NNS 1698 1699 . . . 1700 1709 Therefore therefore RB 1709 1710 , , , 1711 1723 inactivation inactivation NN 1724 1726 of of IN 1727 1730 the the DT 1731 1734 IgH IgH NNP 1735 1736 3 3 CD 1736 1737 ’ ' SYM 1738 1746 enhancer enhancer NN 1747 1749 is be VBZ 1750 1751 a a DT 1752 1766 multifactorial multifactorial JJ 1767 1774 process process NN 1775 1784 affecting affect VBG 1785 1792 several several JJ 1793 1806 transcription transcription NN 1807 1814 factors factor NNS 1815 1819 that that WDT 1820 1827 control control VBP 1828 1831 the the DT 1832 1845 cell-specific cell-specific JJ 1846 1849 and and CC 1850 1863 developmental developmental JJ 1864 1872 activity activity NN 1873 1875 of of IN 1876 1879 the the DT 1880 1888 enhancer enhancer NN 1888 1889 . . .