0 8 Retinoid Retinoid NNP 9 10 X X NNP 11 19 receptor receptor NN 20 21 ( ( ( 21 24 RXR RXR NNP 24 25 ) ) ) 26 41 agonist-induced agonist-induced JJ 42 52 activation activation NN 53 55 of of IN 56 73 dominant-negative dominant-negative JJ 74 86 RXR-retinoic rxr-retinoic JJ 87 91 acid acid NN 92 100 receptor receptor NN 101 109 alpha403 alpha403 NN 110 122 heterodimers heterodimer NNS 123 125 is be VBZ 126 141 developmentally developmentally RB 142 151 regulated regulate VBN 152 158 during during IN 159 166 myeloid myeloid JJ 167 182 differentiation differentiation NN 182 183 . . . 185 188 The the DT 189 197 multiple multiple JJ 198 206 biologic biologic JJ 207 217 activities activity NNS 218 220 of of IN 221 229 retinoic retinoic JJ 230 234 acid acid NN 235 236 ( ( ( 236 238 RA RA NNP 238 239 ) ) ) 240 243 are be VBP 244 252 mediated mediate VBN 253 260 through through IN 261 264 RAR RAR NNP 265 268 and and CC 269 277 retinoid retinoid NN 278 279 X x NN 280 288 receptor receptor NN 289 290 ( ( ( 290 293 RXR RXR NNP 293 294 ) ) ) 295 302 nuclear nuclear JJ 303 312 receptors receptor NNS 313 317 that that WDT 318 326 interact interact VBP 327 331 with with IN 332 340 specific specific JJ 341 344 DNA dna NN 345 351 target target NN 352 361 sequences sequence NNS 362 364 as as IN 365 377 heterodimers heterodimer NNS 378 379 ( ( ( 379 386 RXR-RAR RXR-RAR NNP 386 387 ) ) ) 388 390 or or CC 391 401 homodimers homodimer NNS 402 403 ( ( ( 403 410 RXR-RXR RXR-RXR NNP 410 411 ) ) ) 411 412 . . . 413 415 RA RA NNP 416 424 receptor receptor NN 425 435 activation activation NN 436 443 appears appear VBZ 444 452 critical critical JJ 453 455 to to TO 456 466 regulating regulate VBG 467 476 important important JJ 477 484 aspects aspect NNS 485 487 of of IN 488 501 hematopoiesis hematopoiesis NN 501 502 , , , 503 508 since since IN 509 520 transducing transduce VBG 521 522 a a DT 523 538 COOH-terminally cooh-terminally RB 539 548 truncated truncate VBN 549 557 RARalpha RARalpha NNP 558 568 exhibiting exhibit VBG 569 586 dominant-negative dominant-negative JJ 587 595 activity activity NN 596 597 ( ( ( 597 608 RARalpha403 RARalpha403 NNP 608 609 ) ) ) 610 614 into into IN 615 621 normal normal JJ 622 627 mouse mouse NN 628 632 bone bone NN 633 639 marrow marrow NN 640 649 generates generate VBZ 650 663 hematopoietic hematopoietic JJ 664 670 growth growth NN 671 687 factor-dependent factor-dependent JJ 688 692 cell cell NN 693 698 lines line NNS 699 705 frozen freeze VBN 706 708 at at IN 709 712 the the DT 713 724 multipotent multipotent JJ 725 735 progenitor progenitor NN 736 737 ( ( ( 737 740 EML EML NNP 740 741 ) ) ) 742 744 or or CC 745 754 committed commit VBN 755 767 promyelocyte promyelocyte NN 768 769 ( ( ( 769 773 MPRO mpro NN 773 774 ) ) ) 775 781 stages stage NNS 781 782 . . . 783 795 Nevertheless nevertheless RB 795 796 , , , 797 807 relatively relatively RB 808 812 high high JJ 812 813 , , , 814 829 pharmacological pharmacological JJ 830 844 concentrations concentration NNS 845 847 of of IN 848 850 RA RA NNP 851 852 ( ( ( 852 853 1 1 CD 854 856 to to TO 857 859 10 10 CD 860 861 & & CC 861 866 mgr;M mgr;M NNP 866 867 ) ) ) 868 876 overcome overcome VBP 877 882 these these DT 883 898 differentiation differentiation NN 899 905 blocks block NNS 906 909 and and CC 910 916 induce induce VBP 917 925 terminal terminal JJ 926 938 granulocytic granulocytic JJ 939 954 differentiation differentiation NN 955 957 of of IN 958 961 the the DT 962 966 MPRO mpro NN 967 980 promyelocytes promyelocyte NNS 981 986 while while IN 987 999 potentiating potentiate VBG 1000 1013 interleukin-3 interleukin-3 NN 1014 1015 ( ( ( 1015 1028 IL-3)-induced il-3)-induced JJ 1029 1039 commitment commitment NN 1040 1042 of of IN 1043 1046 EML EML NNP 1047 1052 cells cell NNS 1053 1055 to to TO 1056 1059 the the DT 1060 1080 granulocyte/monocyte granulocyte/monocyte NN 1081 1088 lineage lineage NN 1088 1089 . . . 1090 1092 In in IN 1093 1096 the the DT 1097 1104 present present JJ 1105 1110 study study NN 1110 1111 , , , 1112 1114 we we PRP 1115 1123 utilized utilize VBD 1124 1128 RXR- rxr- NN 1129 1132 and and CC 1133 1145 RAR-specific rar-specific JJ 1146 1154 agonists agonist NNS 1155 1158 and and CC 1159 1170 antagonists antagonist NNS 1171 1173 to to TO 1174 1183 determine determine VB 1184 1187 how how WRB 1188 1190 RA RA NNP 1191 1200 overcomes overcome VBZ 1201 1204 the the DT 1205 1222 dominant-negative dominant-negative JJ 1223 1231 activity activity NN 1232 1234 of of IN 1235 1238 the the DT 1239 1248 truncated truncate VBN 1249 1257 RARalpha RARalpha NNP 1258 1260 in in IN 1261 1266 these these DT 1267 1276 different different JJ 1277 1284 myeloid myeloid JJ 1285 1298 developmental developmental JJ 1299 1305 stages stage NNS 1305 1306 . . . 1307 1319 Unexpectedly unexpectedly RB 1319 1320 , , , 1321 1323 we we PRP 1324 1332 observed observe VBD 1333 1337 that that IN 1338 1340 an an DT 1341 1353 RXR-specific rxr-specific JJ 1353 1354 , , , 1355 1361 rather rather RB 1362 1366 than than IN 1367 1369 an an DT 1370 1382 RAR-specific rar-specific JJ 1382 1383 , , , 1384 1391 agonist agonist NN 1392 1399 induces induce VBZ 1400 1408 terminal terminal JJ 1409 1421 granulocytic granulocytic JJ 1422 1437 differentiation differentiation NN 1438 1440 of of IN 1441 1445 MPRO mpro NN 1446 1459 promyelocytes promyelocyte NNS 1459 1460 , , , 1461 1464 and and CC 1465 1469 this this DT 1470 1485 differentiation differentiation NN 1486 1488 is be VBZ 1489 1499 associated associate VBN 1500 1504 with with IN 1505 1515 activation activation NN 1516 1518 of of IN 1519 1522 DNA DNA NNP 1523 1531 response response NN 1532 1540 elements element NNS 1541 1554 corresponding correspond VBG 1555 1557 to to TO 1558 1565 RAR-RXR rar-rxr NN 1566 1578 heterodimers heterodimer NNS 1579 1585 rather rather RB 1586 1590 than than IN 1591 1598 RXR-RXR rxr-rxr JJ 1599 1609 homodimers homodimer NNS 1609 1610 . . . 1611 1615 This this DT 1616 1619 RXR RXR NNP 1620 1627 agonist agonist NN 1628 1636 activity activity NN 1637 1639 is be VBZ 1640 1647 blocked block VBN 1648 1650 by by IN 1651 1663 RAR-specific rar-specific JJ 1664 1675 antagonists antagonist NNS 1675 1676 , , , 1677 1687 suggesting suggest VBG 1688 1697 extensive extensive JJ 1698 1708 cross-talk cross-talk NN 1709 1716 between between IN 1717 1720 the the DT 1721 1729 partners partner NNS 1730 1732 of of IN 1733 1736 the the DT 1737 1740 RXR RXR NNP 1741 1753 -RARalpha403 -raralpha403 NN 1754 1765 heterodimer heterodimer NN 1765 1766 . . . 1767 1769 In in IN 1770 1778 contrast contrast NN 1778 1779 , , , 1780 1782 in in IN 1783 1786 the the DT 1787 1791 more more RBR 1792 1800 immature immature JJ 1800 1801 , , , 1802 1813 multipotent multipotent JJ 1814 1817 EML EML NNP 1818 1823 cells cell NNS 1824 1826 we we PRP 1827 1835 observed observe VBD 1836 1840 that that IN 1841 1845 this this DT 1846 1858 RXR-specific rxr-specific JJ 1859 1866 agonist agonist NN 1867 1869 is be VBZ 1870 1878 inactive inactive JJ 1879 1885 either either CC 1886 1888 in in IN 1889 1901 potentiating potentiate VBG 1902 1915 IL-3-mediated il-3-mediated JJ 1916 1926 commitment commitment NN 1927 1929 of of IN 1930 1933 EML EML NNP 1934 1939 cells cell NNS 1940 1942 to to TO 1943 1946 the the DT 1947 1958 granulocyte granulocyte NN 1959 1966 lineage lineage NN 1967 1969 or or CC 1970 1972 in in IN 1973 1988 transactivating transactivate VBG 1989 1996 RAR-RXR RAR-RXR NNP 1997 2005 response response NN 2006 2014 elements element NNS 2014 2015 . . . 2016 2019 RA- RA- NNP 2020 2029 triggered trigger VBD 2030 2045 GALdbd-RARalpha GALdbd-RARalpha NNP 2046 2052 hybrid hybrid NN 2053 2061 activity activity NN 2062 2064 in in IN 2065 2070 these these DT 2071 2076 cells cell NNS 2077 2086 indicates indicate VBZ 2087 2091 that that IN 2092 2095 the the DT 2096 2107 multipotent multipotent JJ 2108 2111 EML EML NNP 2112 2117 cells cell NNS 2118 2124 harbor harbor VBP 2125 2136 substantial substantial JJ 2137 2144 nuclear nuclear JJ 2145 2152 hormone hormone NN 2153 2161 receptor receptor NN 2162 2173 coactivator coactivator NN 2174 2182 activity activity NN 2182 2183 . . . 2184 2191 However however RB 2191 2192 , , , 2193 2196 the the DT 2197 2204 histone histone NN 2205 2216 deacetylase deacetylase NN 2217 2218 ( ( ( 2218 2222 HDAC HDAC NNP 2222 2223 ) ) ) 2224 2233 inhibitor inhibitor NN 2234 2246 trichostatin trichostatin NN 2247 2248 A a NN 2249 2256 readily readily RB 2257 2266 activates activate VBZ 2267 2269 an an DT 2270 2277 RXR-RAR rxr-rar NN 2278 2286 reporter reporter NN 2287 2296 construct construct NN 2297 2299 in in IN 2300 2303 the the DT 2304 2315 multipotent multipotent JJ 2316 2319 EML EML NNP 2320 2325 cells cell NNS 2326 2329 but but CC 2330 2333 not not RB 2334 2336 in in IN 2337 2340 the the DT 2341 2350 committed commit VBN 2351 2355 MPRO mpro NN 2356 2369 promyelocytes promyelocyte NNS 2369 2370 , , , 2371 2381 indicating indicate VBG 2382 2386 that that IN 2387 2398 differences difference NNS 2399 2401 in in IN 2402 2417 HDAC-containing hdac-containing JJ 2418 2427 repressor repressor NN 2428 2437 complexes complex NNS 2438 2440 in in IN 2441 2446 these these DT 2447 2450 two two CD 2451 2458 closely closely RB 2459 2466 related related JJ 2467 2470 but but CC 2471 2479 distinct distinct JJ 2480 2493 hematopoietic hematopoietic JJ 2494 2502 lineages lineage NNS 2503 2508 might might MD 2509 2516 account account VB 2517 2520 for for IN 2521 2524 the the DT 2525 2537 differential differential JJ 2538 2548 activation activation NN 2549 2551 of of IN 2552 2555 the the DT 2556 2571 RXR-RARalpha403 rxr-raralpha403 NN 2572 2584 heterodimers heterodimer NNS 2585 2589 that that WDT 2590 2592 we we PRP 2593 2601 observed observe VBD 2602 2604 at at IN 2605 2610 these these DT 2611 2620 different different JJ 2621 2627 stages stage NNS 2628 2630 of of IN 2631 2638 myeloid myeloid JJ 2639 2650 development development NN 2650 2651 . . .