0 8 Retinoic retinoic JJ 9 13 acid acid NN 14 23 activates activate VBZ 24 34 interferon interferon NN 35 45 regulatory regulatory JJ 46 54 factor-1 factor-1 NN 55 59 gene gene NN 60 70 expression expression NN 71 73 in in IN 74 81 myeloid myeloid JJ 82 87 cells cell NNS 87 88 . . . 90 108 All-trans-retinoic all-trans-retinoic JJ 109 113 acid acid NN 114 115 ( ( ( 115 119 ATRA ATRA NNP 119 120 ) ) ) 121 123 is be VBZ 124 127 the the DT 128 132 drug drug NN 133 135 of of IN 136 142 choice choice NN 143 145 in in IN 146 149 the the DT 150 159 treatment treatment NN 160 162 of of IN 163 168 acute acute JJ 169 182 promyelocytic promyelocytic JJ 183 191 leukemia leukemia NN 192 193 ( ( ( 193 196 APL APL NNP 196 197 ) ) ) 197 198 . . . 199 203 ATRA ATRA NNP 204 211 induces induce VBZ 212 216 both both CC 217 219 in in FW 220 225 vitro vitro FW 226 229 and and CC 230 232 in in FW 233 237 vivo vivo FW 238 253 differentiation differentiation NN 254 256 of of IN 257 260 APL APL NNP 261 266 cells cell NNS 267 271 into into IN 272 278 mature mature JJ 279 291 granulocytes granulocyte NNS 291 292 . . . 293 300 However however RB 300 301 , , , 302 305 the the DT 306 315 molecular molecular JJ 316 326 mechanisms mechanism NNS 327 335 involved involve VBN 336 338 in in IN 339 353 ATRA-dependent atra-dependent JJ 354 360 growth growth NN 361 371 inhibition inhibition NN 372 375 and and CC 376 384 cellular cellular JJ 385 400 differentiation differentiation NN 401 404 are be VBP 405 408 not not RB 409 418 presently presently RB 419 429 understood understand VBN 429 430 . . . 431 434 The the DT 435 438 NB4 nb4 NN 439 443 cell cell NN 444 448 line line NN 448 449 , , , 450 455 which which WDT 456 458 is be VBZ 459 466 derived derive VBN 467 471 from from IN 472 475 the the DT 476 480 bone bone NN 481 487 marrow marrow NN 488 490 of of IN 491 492 a a DT 493 500 patient patient NN 501 505 with with IN 506 509 APL APL NNP 510 516 during during IN 517 524 relapse relapse NN 524 525 , , , 526 529 can can MD 530 532 be be VB 533 537 used use VBN 538 540 as as IN 541 542 a a DT 543 548 model model NN 549 555 system system NN 556 558 to to TO 559 564 study study VB 565 568 the the DT 569 575 growth growth NN 576 579 and and CC 580 595 differentiation differentiation NN 596 598 of of IN 599 602 APL APL NNP 603 608 cells cell NNS 608 609 . . . 610 617 Because because IN 618 628 interferon interferon NN 629 630 ( ( ( 630 633 IFN IFN NNP 633 634 ) ) ) 635 645 regulatory regulatory JJ 646 653 factors factor NNS 654 655 ( ( ( 655 660 IRF-1 IRF-1 NNP 661 664 and and CC 665 670 IRF-2 irf-2 NN 670 671 ) ) ) 672 675 and and CC 676 681 other other JJ 682 695 IFN-inducible ifn-inducible JJ 696 700 gene gene NN 701 709 products product NNS 710 718 regulate regulate VBP 719 723 cell cell NN 724 730 growth growth NN 730 731 , , , 732 734 we we PRP 735 743 analyzed analyze VBD 744 747 the the DT 748 755 effects effect NNS 756 758 of of IN 759 763 ATRA ATRA NNP 764 766 on on IN 767 770 the the DT 771 781 expression expression NN 782 784 of of IN 785 790 these these DT 791 796 genes gene NNS 796 797 . . . 798 800 We we PRP 801 805 show show VBP 806 810 that that IN 811 815 ATRA ATRA NNP 816 824 directly directly RB 825 834 activates activate VBZ 835 840 IRF-1 irf-1 NN 841 845 gene gene NN 846 856 expression expression NN 856 857 , , , 858 866 followed follow VBN 867 869 by by IN 870 880 activation activation NN 881 883 of of IN 884 889 IRF-2 irf-2 NN 890 893 and and CC 894 898 2’-5 2'-5 NN 898 899 ’ ' POS 900 914 oligoadenylate oligoadenylate NN 915 925 synthetase synthetase NN 926 927 ( ( ( 927 930 OAS OAS NNP 930 931 ) ) ) 932 936 gene gene NN 937 947 expression expression NN 948 952 with with IN 953 959 slower slow JJR 960 968 kinetics kinetic NNS 968 969 . . . 970 972 In in IN 973 981 addition addition NN 982 984 to to TO 985 988 NB4 nb4 NN 989 994 cells cell NNS 994 995 , , , 996 1000 ATRA ATRA NNP 1001 1005 also also RB 1006 1015 activated activate VBD 1016 1021 IRF-1 irf-1 NN 1022 1026 gene gene NN 1027 1037 expression expression NN 1038 1040 in in IN 1041 1046 HL-60 HL-60 NNP 1046 1047 , , , 1048 1052 U937 U937 NNP 1052 1053 , , , 1054 1057 and and CC 1058 1063 THP-1 thp-1 NN 1064 1069 cells cell NNS 1069 1070 , , , 1071 1076 which which WDT 1077 1080 all all DT 1081 1088 respond respond VBP 1089 1091 to to TO 1092 1096 ATRA ATRA NNP 1097 1099 by by IN 1100 1106 growth growth NN 1107 1117 inhibition inhibition NN 1117 1118 . . . 1119 1120 A a DT 1121 1125 more more JJR 1126 1130 than than IN 1131 1139 additive additive JJ 1140 1148 increase increase NN 1149 1151 in in IN 1152 1157 IRF-1 irf-1 NN 1158 1162 gene gene NN 1163 1173 expression expression NN 1174 1177 was be VBD 1178 1182 seen see VBN 1183 1187 with with IN 1188 1192 ATRA ATRA NNP 1193 1196 and and CC 1197 1206 IFN-gamma IFN-gamma NNP 1207 1209 in in IN 1210 1213 NB4 nb4 NN 1214 1219 cells cell NNS 1219 1220 . . . 1221 1225 ATRA ATRA NNP 1226 1229 did do VBD 1230 1233 not not RB 1234 1242 activate activate VB 1243 1250 nuclear nuclear JJ 1251 1257 factor factor NN 1258 1263 kappa kappa NN 1264 1265 B B NNP 1266 1268 or or CC 1269 1275 signal signal NN 1276 1286 transducer transducer NN 1287 1290 and and CC 1291 1300 activator activator NN 1301 1303 of of IN 1304 1317 transcription transcription NN 1318 1319 ( ( ( 1319 1323 STAT STAT NNP 1323 1324 ) ) ) 1325 1335 activation activation NN 1336 1344 pathways pathway NNS 1344 1345 , , , 1346 1356 suggesting suggest VBG 1357 1361 that that IN 1362 1364 an an DT 1365 1374 alternate alternate JJ 1375 1384 mechanism mechanism NN 1385 1387 is be VBZ 1388 1396 involved involve VBN 1397 1399 in in IN 1400 1405 IRF-1 irf-1 NN 1406 1410 gene gene NN 1411 1421 activation activation NN 1421 1422 . . . 1423 1426 The the DT 1427 1439 ATRA-induced atra-induced JJ 1440 1450 expression expression NN 1451 1453 of of IN 1454 1459 IRF-1 IRF-1 NNP 1459 1460 , , , 1461 1463 an an DT 1464 1473 activator activator NN 1474 1476 of of IN 1477 1490 transcription transcription NN 1491 1494 and and CC 1495 1504 repressor repressor NN 1505 1507 of of IN 1508 1522 transformation transformation NN 1522 1523 , , , 1524 1527 may may MD 1528 1530 be be VB 1531 1534 one one CD 1535 1537 of of IN 1538 1541 the the DT 1542 1551 molecular molecular JJ 1552 1562 mechanisms mechanism NNS 1563 1565 of of IN 1566 1578 ATRA-induced atra-induced JJ 1579 1585 growth growth NN 1586 1596 inhibition inhibition NN 1596 1597 , , , 1598 1601 and and CC 1602 1605 the the DT 1606 1611 basis basis NN 1612 1615 for for IN 1616 1619 the the DT 1620 1631 synergistic synergistic JJ 1632 1639 actions action NNS 1640 1642 of of IN 1643 1647 ATRA ATRA NNP 1648 1651 and and CC 1652 1656 IFNs IFN NNP 1657 1659 in in IN 1660 1667 myeloid myeloid JJ 1668 1676 leukemia leukemia NN 1677 1682 cells cell NNS 1682 1683 . . .