0 8 Retinoic retinoic JJ 9 13 acid acid NN 14 27 downmodulates downmodulate VBZ 28 37 erythroid erythroid JJ 38 53 differentiation differentiation NN 54 57 and and CC 58 63 GATA1 gata1 NN 64 74 expression expression NN 75 77 in in IN 78 86 purified purify VBN 87 103 adult-progenitor adult-progenitor JJ 104 111 culture culture NN 111 112 . . . 114 123 All-trans all-trans JJ 124 132 retinoic retinoic JJ 133 137 acid acid NN 138 139 ( ( ( 139 141 RA RA NNP 141 142 ) ) ) 143 145 is be VBZ 146 148 an an DT 149 158 important important JJ 159 168 morphogen morphogen NN 169 171 in in IN 172 182 vertebrate vertebrate NN 183 194 development development NN 194 195 , , , 196 197 a a DT 198 204 normal normal JJ 205 216 constituent constituent NN 217 219 in in IN 220 225 human human JJ 226 231 adult adult JJ 232 237 blood blood NN 238 241 and and CC 242 244 is be VBZ 245 249 also also RB 250 258 involved involve VBN 259 261 in in IN 262 265 the the DT 266 273 control control NN 274 276 of of IN 277 281 cell cell NN 282 288 growth growth NN 289 292 and and CC 293 308 differentiation differentiation NN 309 311 in in IN 312 317 acute acute JJ 318 331 promyelocytic promyelocytic JJ 332 340 leukemia leukemia NN 340 341 . . . 342 344 We we PRP 345 349 have have VBP 350 358 examined examine VBN 359 362 the the DT 363 370 effects effect NNS 371 373 of of IN 374 376 RA RA NNP 377 379 on on IN 380 386 normal normal JJ 387 400 hematopoiesis hematopoiesis NN 401 403 by by IN 404 409 using use VBG 410 415 early early JJ 416 429 hematopoietic hematopoietic JJ 430 440 progenitor progenitor NN 441 446 cells cell NNS 447 448 ( ( ( 448 451 HPC HPC NNP 451 452 ) ) ) 453 464 stringently stringently RB 465 473 purified purify VBN 474 478 from from IN 479 484 adult adult JJ 485 495 peripheral peripheral JJ 496 501 blood blood NN 501 502 . . . 503 505 In in IN 506 518 clonogenetic clonogenetic JJ 519 524 fetal fetal JJ 525 529 calf calf NN 530 548 serum-supplemented serum-supplemented JJ 549 550 ( ( ( 550 554 FCS+ fcs+ JJ 554 555 ) ) ) 556 558 or or CC 559 575 -nonsupplemented -nonsupplemented JJ 576 577 ( ( ( 577 581 FCS- fcs- JJ 581 582 ) ) ) 583 590 culture culture NN 591 598 treated treat VBN 599 603 with with IN 604 614 saturating saturating JJ 615 621 levels level NNS 622 624 of of IN 625 638 interleukin-3 interleukin-3 NN 639 640 ( ( ( 640 644 IL-3 IL-3 NNP 644 645 ) ) ) 646 668 granulocyte-macrophage granulocyte-macrophage JJ 669 687 colony-stimulating colony-stimulating JJ 688 694 factor factor NN 695 696 ( ( ( 696 702 GM-CSF GM-CSF NNP 702 703 ) ) ) 704 707 and and CC 708 722 erythropoietin erythropoietin NN 723 724 ( ( ( 724 726 Ep Ep NNP 726 727 ) ) ) 728 729 ( ( ( 729 737 combined combine VBN 738 742 with with IN 743 748 c-kit c-kit NN 749 755 ligand ligand NN 756 758 in in IN 759 773 FCS(-)-culture FCS(-)-culture NNP 774 784 conditions condition NNS 784 785 ) ) ) 785 786 , , , 787 789 RA RA NNP 790 797 induces induce VBZ 798 799 a a DT 800 808 dramatic dramatic JJ 809 823 dose-dependent dose-dependent JJ 824 829 shift shift NN 830 834 from from IN 835 844 erythroid erythroid JJ 845 847 to to TO 848 864 granulomonocytic granulomonocytic JJ 865 871 colony colony NN 872 881 formation formation NN 881 882 , , , 883 886 the the DT 887 893 latter latter JJ 894 902 colonies colony NNS 903 908 being be VBG 909 920 essentially essentially RB 921 932 represented represent VBN 933 935 by by IN 936 948 granulocytic granulocytic JJ 949 955 clones clone NNS 955 956 . . . 957 961 This this DT 962 967 shift shift NN 968 970 is be VBZ 971 981 apparently apparently RB 982 985 not not RB 986 992 caused cause VBN 993 995 by by IN 996 997 a a DT 998 1009 recruitment recruitment NN 1010 1020 phenomenon phenomenon NN 1020 1021 , , , 1022 1029 because because IN 1030 1032 in in IN 1033 1037 FCS+ fcs+ JJ 1038 1045 culture culture NN 1045 1046 , , , 1047 1050 the the DT 1051 1056 total total JJ 1057 1063 number number NN 1064 1066 of of IN 1067 1075 colonies colony NNS 1076 1078 is be VBZ 1079 1082 not not RB 1083 1096 significantly significantly RB 1097 1105 modified modify VBN 1106 1108 by by IN 1109 1111 RA RA NNP 1112 1120 addition addition NN 1120 1121 . . . 1122 1124 In in IN 1125 1129 FCS- fcs- NN 1130 1147 liquid-suspension liquid-suspension NN 1148 1155 culture culture NN 1156 1168 supplemented supplement VBN 1169 1173 with with IN 1174 1184 saturating saturate VBG 1185 1187 Ep Ep NNP 1188 1193 level level NN 1194 1197 and and CC 1198 1206 low-dose low-dose JJ 1207 1218 IL-3/GM-CSF IL-3/GM-CSF NNP 1218 1219 , , , 1220 1225 adult adult JJ 1226 1229 HPC HPC NNP 1230 1237 undergo undergo VBP 1238 1248 unilineage unilineage JJ 1249 1263 erythropoietic erythropoietic JJ 1264 1279 differentiation differentiation NN 1279 1280 : : : 1281 1285 Here here RB 1286 1291 again again RB 1291 1292 , , , 1293 1302 treatment treatment NN 1303 1307 with with IN 1308 1317 high-dose high-dose JJ 1318 1320 RA RA NNP 1321 1328 induces induce VBZ 1329 1330 a a DT 1331 1336 shift shift NN 1337 1341 from from IN 1342 1345 the the DT 1346 1355 erythroid erythroid JJ 1356 1358 to to TO 1359 1371 granulocytic granulocytic JJ 1372 1387 differentiation differentiation NN 1388 1395 pathway pathway NN 1395 1396 . . . 1397 1404 Studies Study NNPS 1405 1407 on on IN 1408 1410 RA RA NNP 1411 1424 time-response time-response JJ 1425 1427 or or CC 1428 1433 pulse pulse NN 1434 1443 treatment treatment NN 1444 1446 in in IN 1447 1456 semisolid semisolid JJ 1457 1459 or or CC 1460 1466 liquid liquid JJ 1467 1474 culture culture NN 1475 1479 show show VBP 1480 1484 that that IN 1485 1490 early early JJ 1491 1493 RA RA NNP 1494 1502 addition addition NN 1503 1505 is be VBZ 1506 1510 most most RBS 1511 1520 effective effective JJ 1520 1521 , , , 1522 1526 thus thus RB 1527 1537 indicating indicate VBG 1538 1542 that that IN 1543 1548 early early JJ 1549 1552 but but CC 1553 1556 not not RB 1557 1561 late late JJ 1562 1565 HPC HPC NNP 1566 1569 are be VBP 1570 1579 sensitive sensitive JJ 1580 1582 to to TO 1583 1586 its its PRP$ 1587 1593 action action NN 1593 1594 . . . 1595 1597 We we PRP 1598 1602 then then RB 1603 1611 analyzed analyze VBD 1612 1615 the the DT 1616 1626 expression expression NN 1627 1629 of of IN 1630 1633 the the DT 1634 1640 master master NN 1641 1646 GATA1 gata1 NN 1647 1651 gene gene NN 1651 1652 , , , 1653 1658 which which WDT 1659 1666 encodes encode VBZ 1667 1668 a a DT 1669 1675 finger finger NN 1676 1689 transcription transcription NN 1690 1696 factor factor NN 1697 1705 required require VBN 1706 1709 for for IN 1710 1716 normal normal JJ 1717 1726 erythroid erythroid JJ 1727 1738 development development NN 1738 1739 ; ; : 1740 1748 addition addition NN 1749 1751 of of IN 1752 1754 RA RA NNP 1755 1757 to to TO 1758 1761 HPC HPC NNP 1762 1772 stimulated stimulate VBN 1773 1777 into into IN 1778 1788 unilineage unilineage JJ 1789 1803 erythropoietic erythropoietic JJ 1804 1819 differentiation differentiation NN 1820 1822 in in IN 1823 1829 liquid liquid JJ 1830 1837 culture culture NN 1838 1844 caused cause VBD 1845 1846 a a DT 1847 1856 virtually virtually RB 1857 1865 complete complete JJ 1866 1876 inhibition inhibition NN 1877 1879 of of IN 1880 1885 GATA1 gata1 NN 1886 1890 mRNA mrna NN 1891 1900 induction induction NN 1900 1901 . . . 1902 1907 These these DT 1908 1915 results result NNS 1916 1924 indicate indicate VBP 1925 1929 that that IN 1930 1932 RA RA NNP 1933 1941 directly directly RB 1942 1950 inhibits inhibit VBZ 1951 1954 the the DT 1955 1964 erythroid erythroid JJ 1965 1980 differentiation differentiation NN 1981 1988 program program NN 1989 1991 at at IN 1992 1995 the the DT 1996 2001 level level NN 2002 2004 of of IN 2005 2010 early early JJ 2011 2016 adult adult JJ 2017 2020 HPC HPC NNP 2020 2021 , , , 2022 2025 and and CC 2026 2029 may may MD 2030 2034 lead lead VB 2035 2037 to to TO 2038 2039 a a DT 2040 2045 shift shift NN 2046 2050 from from IN 2051 2054 the the DT 2055 2064 erythroid erythroid JJ 2065 2067 to to TO 2068 2080 granulocytic granulocytic JJ 2081 2096 differentiation differentiation NN 2097 2104 pathway pathway NN 2104 2105 . . . 2106 2110 This this DT 2111 2121 phenomenon phenomenon NN 2122 2124 is be VBZ 2125 2135 correlated correlate VBN 2136 2140 with with IN 2141 2151 inhibition inhibition NN 2152 2154 of of IN 2155 2160 GATA1 gata1 NN 2161 2170 induction induction NN 2171 2173 in in IN 2174 2177 the the DT 2178 2183 early early JJ 2184 2190 stages stage NNS 2191 2193 of of IN 2194 2208 erythropoietic erythropoietic JJ 2209 2224 differentiation differentiation NN 2224 2225 . . .