0 1 [ [ ( 1 3 An an DT 4 18 overexpression overexpression NN 19 21 of of IN 22 30 retinoic retinoic JJ 31 35 acid acid NN 36 44 receptor receptor NN 45 50 alpha alpha NN 51 57 blocks block VBZ 58 65 myeloid myeloid JJ 66 70 cell cell NN 71 86 differentiation differentiation NN 87 89 at at IN 90 93 the the DT 94 106 promyelocyte promyelocyte JJ 107 112 stage stage NN 112 113 ] ] ) 115 123 Retinoic retinoic JJ 124 128 acid acid NN 129 130 ( ( ( 130 132 RA RA NNP 132 133 ) ) ) 133 134 , , , 135 136 a a DT 137 144 vitamin vitamin NN 145 146 A a NN 147 157 derivative derivative NN 157 158 , , , 159 165 exerts exert VBZ 166 167 a a DT 168 172 wide wide JJ 173 178 range range NN 179 181 of of IN 182 192 biological biological JJ 193 200 effects effect NNS 201 208 related relate VBN 209 211 to to TO 212 216 cell cell NN 217 230 proliferation proliferation NN 231 234 and and CC 235 250 differentiation differentiation NN 250 251 . . . 252 255 The the DT 256 267 pleiotropic pleiotropic JJ 268 275 effects effect NNS 276 278 of of IN 279 281 RA RA NNP 282 285 are be VBP 286 293 thought think VBN 294 296 to to TO 297 299 be be VB 300 308 mediated mediate VBN 309 316 through through IN 317 325 specific specific JJ 326 333 nuclear nuclear JJ 334 336 RA RA NNP 337 346 receptors receptor NNS 347 348 ( ( ( 348 352 RARs RAR NNP 352 353 ) ) ) 353 354 . . . 355 359 RARs rar NNS 360 363 are be VBP 364 371 members member NNS 372 374 of of IN 375 378 the the DT 379 394 steroid/thyroid steroid/thyroid JJ 395 402 hormone hormone NN 403 411 receptor receptor NN 412 423 superfamily superfamily NN 424 427 and and CC 428 435 exhibit exhibit VBP 436 437 a a DT 438 447 molecular molecular JJ 448 457 structure structure NN 458 462 that that WDT 463 470 possess possess VBP 471 479 discrete discrete JJ 480 491 DNA-binding dna-binding JJ 492 495 and and CC 496 498 RA RA NNP 499 500 ( ( ( 500 515 ligand)-binding ligand)-binding JJ 516 523 domains domain NNS 523 524 . . . 525 527 In in IN 528 541 hematopoietic hematopoietic JJ 542 548 system system NN 548 549 , , , 550 552 RA RA NNP 553 556 and and CC 557 561 RARs RAR NNP 561 562 , , , 563 576 predominantly predominantly RB 577 580 RAR rar NN 581 586 alpha alpha NN 587 590 may may MD 591 595 play play VB 596 599 key key JJ 600 605 roles role NNS 606 609 for for IN 610 613 the the DT 614 627 proliferation proliferation NN 628 631 and and CC 632 647 differentiation differentiation NN 648 650 of of IN 651 664 hematopoietic hematopoietic JJ 665 676 progenitors progenitor NNS 676 677 . . . 678 685 However however RB 685 686 , , , 687 689 it it PRP 690 692 is be VBZ 693 702 currently currently RB 703 710 unknown unknown JJ 711 714 how how WRB 715 717 RA RA NNP 718 721 and and CC 722 726 RARs RAR NNP 727 730 are be VBP 731 739 involved involve VBN 740 742 in in IN 743 753 regulating regulate VBG 754 760 normal normal JJ 761 774 hematopoietic hematopoietic JJ 775 790 differentiation differentiation NN 790 791 . . . 792 794 To to TO 795 799 make make VB 800 805 clear clear JJ 806 809 the the DT 810 815 roles role NNS 816 818 of of IN 819 821 RA RA NNP 822 825 and and CC 826 829 RAR RAR NNP 830 835 alpha alpha NN 836 838 in in IN 839 842 the the DT 843 849 normal normal JJ 850 863 hematopoiesis hematopoiesis NN 863 864 , , , 865 866 I I PRP 867 871 have have VBP 872 882 introduced introduce VBN 883 886 the the DT 887 896 construct construct NN 897 899 of of IN 900 905 human human JJ 906 909 RAR rar NN 910 915 alpha alpha NN 916 917 ( ( ( 917 921 hRAR hRAR NNP 922 927 alpha alpha NN 927 928 ) ) ) 929 933 into into IN 934 940 murine murine JJ 941 945 bone bone NN 946 952 marrow marrow NN 953 958 cells cell NNS 959 963 with with IN 964 974 retroviral retroviral JJ 975 981 vector vector NN 981 982 , , , 983 986 and and CC 987 995 selected select VBN 996 1004 infected infected JJ 1005 1010 cells cell NNS 1011 1015 with with IN 1016 1020 drug drug NN 1021 1030 resistant resistant JJ 1031 1037 marker marker NN 1038 1039 ( ( ( 1039 1046 Neo(r)) Neo(r)) NNP 1047 1055 cultured culture VBN 1056 1058 on on IN 1059 1062 the the DT 1063 1069 stroma stroma NN 1070 1074 cell cell NN 1075 1079 line line NN 1080 1081 ( ( ( 1081 1088 PA6-neo PA6-neo NNP 1088 1089 ) ) ) 1089 1090 , , , 1091 1094 and and CC 1095 1103 analyzed analyze VBD 1104 1107 the the DT 1108 1116 behavior behavior NN 1117 1119 of of IN 1120 1128 infected infected JJ 1129 1134 cells cell NNS 1134 1135 . . . 1136 1139 All all DT 1140 1142 of of IN 1143 1152 procedure procedure NN 1153 1157 were be VBD 1158 1162 done do VBN 1163 1165 in in FW 1166 1171 vitro vitro FW 1171 1172 . . . 1173 1177 Most most JJS 1178 1183 cells cell NNS 1184 1192 infected infect VBN 1193 1197 with with IN 1198 1202 hRAR hRAR NNP 1203 1208 alpha alpha NN 1209 1218 exhibited exhibit VBD 1219 1232 promyelocytic promyelocytic JJ 1233 1243 morphology morphology NN 1244 1247 and and CC 1248 1252 were be VBD 1253 1260 thought think VBN 1261 1263 to to TO 1264 1266 be be VB 1267 1274 blocked block VBN 1275 1277 at at IN 1278 1281 the the DT 1282 1295 promyelocytic promyelocytic JJ 1296 1301 stage stage NN 1302 1304 in in IN 1305 1310 their their PRP$ 1311 1318 myeloid myeloid JJ 1319 1334 differentiation differentiation NN 1334 1335 . . . 1336 1347 Furthermore furthermore RB 1347 1348 , , , 1349 1354 these these DT 1355 1363 immature immature JJ 1364 1369 cells cell NNS 1370 1384 differentiated differentiate VBD 1385 1395 terminally terminally RB 1396 1400 into into IN 1401 1407 mature mature JJ 1408 1420 granulocytes granulocyte NNS 1421 1423 by by IN 1424 1430 adding add VBG 1431 1435 with with IN 1436 1438 RA RA NNP 1439 1440 ( ( ( 1440 1446 10(-6) 10(-6) CD 1447 1448 M M NNP 1448 1449 ) ) ) 1449 1450 . . . 1451 1454 RAR RAR NNP 1455 1460 alpha alpha NN 1461 1469 infected infected JJ 1470 1475 cells cell NNS 1476 1480 were be VBD 1481 1485 also also RB 1486 1490 able able JJ 1491 1493 to to TO 1494 1507 differentiate differentiate VB 1508 1512 into into IN 1513 1519 mature mature JJ 1520 1531 macrophages macrophage NNS 1532 1534 in in IN 1535 1538 the the DT 1539 1543 both both NN 1544 1546 of of IN 1547 1551 long long JJ 1552 1556 term term NN 1557 1564 culture culture NN 1565 1568 and and CC 1569 1572 IL3 il3 NN 1573 1579 colony colony NN 1579 1580 . . . 1581 1586 These these DT 1587 1599 observations observation NNS 1600 1607 suggest suggest VBP 1608 1612 that that IN 1613 1615 an an DT 1616 1630 overexpression overexpression NN 1631 1633 of of IN 1634 1637 RAR RAR NNP 1638 1643 alpha alpha NN 1644 1649 alone alone RB 1650 1652 is be VBZ 1653 1662 effective effective JJ 1663 1665 to to TO 1666 1674 suppress suppress VB 1675 1682 myeloid myeloid JJ 1683 1687 cell cell NN 1688 1703 differentiation differentiation NN 1704 1707 and and CC 1708 1711 RAR rar NN 1712 1717 alpha alpha NN 1718 1723 plays play VBZ 1724 1725 a a DT 1726 1733 crucial crucial JJ 1734 1738 role role NN 1739 1741 in in IN 1742 1745 the the DT 1746 1754 terminal terminal JJ 1755 1770 differentiation differentiation NN 1771 1773 of of IN 1774 1781 myeloid myeloid JJ 1782 1792 precursors precursor NNS 1792 1793 . . . 1794 1797 The the DT 1798 1804 system system NN 1805 1814 described describe VBN 1815 1819 here here RB 1820 1823 may may MD 1824 1829 serve serve VB 1830 1832 as as IN 1833 1834 a a DT 1835 1840 model model NN 1841 1844 for for IN 1845 1853 studying study VBG 1854 1857 the the DT 1858 1861 the the DT 1862 1871 essential essential JJ 1872 1877 genes gene NNS 1878 1881 for for IN 1882 1897 differentiation differentiation NN 1898 1900 of of IN 1901 1907 normal normal JJ 1908 1912 bone bone NN 1913 1919 marrow marrow NN 1920 1925 cells cell NNS 1925 1926 . . .