0 9 MDS1/EVI1 MDS1/EVI1 NNP 10 18 enhances enhance VBZ 19 28 TGF-beta1 tgf-beta1 NN 29 38 signaling signaling NN 39 42 and and CC 43 54 strengthens strengthen VBZ 55 58 its its PRP$ 59 76 growth-inhibitory growth-inhibitory JJ 77 83 effect effect NN 84 87 but but CC 88 91 the the DT 92 111 leukemia-associated leukemia-associated JJ 112 118 fusion fusion NN 119 126 protein protein NN 127 141 AML1/MDS1/EVI1 aml1/mds1/evi1 NN 141 142 , , , 143 150 product product NN 151 153 of of IN 154 157 the the DT 158 165 t(3;21) t(3;21) NN 165 166 , , , 167 176 abrogates abrogate VBZ 177 194 growth-inhibition growth-inhibition NN 195 197 in in IN 198 206 response response NN 207 209 to to TO 210 219 TGF-beta1 TGF-beta1 NNP 219 220 . . . 222 231 MDS1/EVI1 MDS1/EVI1 NNP 231 232 , , , 233 240 located located JJ 241 243 on on IN 244 254 chromosome chromosome NN 255 256 3 3 CD 257 261 band band NN 262 265 q26 q26 NN 265 266 , , , 267 274 encodes encode VBZ 275 276 a a DT 277 288 zinc-finger zinc-finger JJ 289 300 DNA-binding dna-binding JJ 301 314 transcription transcription NN 315 324 activator activator NN 325 328 not not RB 329 337 detected detect VBN 338 340 in in IN 341 347 normal normal JJ 348 361 hematopoietic hematopoietic JJ 362 367 cells cell NNS 368 371 but but CC 372 381 expressed express VBN 382 384 in in IN 385 392 several several JJ 393 399 normal normal JJ 400 407 tissues tissue NNS 407 408 . . . 409 418 MDS1/EVI1 MDS1/EVI1 NNP 419 421 is be VBZ 422 437 inappropriately inappropriately RB 438 447 activated activate VBN 448 450 in in IN 451 458 myeloid myeloid JJ 459 468 leukemias leukemia NNS 469 478 following follow VBG 479 490 chromosomal chromosomal JJ 491 505 rearrangements rearrangement NNS 506 515 involving involve VBG 516 520 band band NN 521 525 3q26 3q26 NN 525 526 . . . 527 530 The the DT 531 545 rearrangements rearrangement NNS 546 550 lead lead VBP 551 557 either either CC 558 560 to to TO 561 565 gene gene NN 566 576 truncation truncation NN 576 577 , , , 578 581 and and CC 582 584 to to TO 585 595 expression expression NN 596 598 of of IN 599 602 the the DT 603 616 transcription transcription NN 617 626 repressor repressor NN 627 631 EVI1 evi1 NN 631 632 , , , 633 635 as as IN 636 640 seen see VBN 641 643 in in IN 644 647 the the DT 648 663 t(3;3)(q21;q26) t(3;3)(q21;q26) NNP 664 667 and and CC 668 682 inv(3)(q21q26) inv(3)(q21q26) NNP 682 683 , , , 684 686 or or CC 687 689 to to TO 690 694 gene gene NN 695 701 fusion fusion NN 701 702 , , , 703 705 as as IN 706 710 seen see VBN 711 713 in in IN 714 717 the the DT 718 734 t(3;21)(q26;q22) t(3;21)(q26;q22) NN 735 740 which which WDT 741 748 results result VBZ 749 751 in in IN 752 755 the the DT 756 762 fusion fusion NN 763 770 protein protein NN 771 785 AML1/MDS1/EVI1 aml1/mds1/evi1 NN 785 786 . . . 787 791 This this DT 792 798 fusion fusion NN 799 806 protein protein NN 807 815 contains contain VBZ 816 819 the the DT 820 831 DNA-binding dna-binding JJ 832 838 domain domain NN 839 841 of of IN 842 845 the the DT 846 859 transcription transcription NN 860 866 factor factor NN 867 871 AML1 aml1 NN 872 877 fused fuse VBN 878 886 in-frame in-frame JJ 887 889 to to TO 890 893 the the DT 894 900 entire entire JJ 901 910 MDS1/EVI1 mds1/evi1 NN 911 915 with with IN 916 919 the the DT 920 929 exclusion exclusion NN 930 932 of of IN 933 936 its its PRP$ 937 942 first first JJ 943 945 12 12 CD 946 951 amino amino NN 952 957 acids acid NNS 957 958 . . . 959 961 In in IN 962 966 this this DT 967 973 report report NN 973 974 , , , 975 977 we we PRP 978 982 have have VBP 983 991 analyzed analyze VBN 992 995 the the DT 996 1004 response response NN 1005 1007 of of IN 1008 1011 the the DT 1012 1025 hematopoietic hematopoietic JJ 1026 1035 precursor precursor NN 1036 1040 cell cell NN 1041 1045 line line NN 1046 1052 32Dcl3 32dcl3 NN 1052 1053 , , , 1054 1064 expressing express VBG 1065 1071 either either CC 1072 1075 the the DT 1076 1082 normal normal JJ 1083 1090 protein protein NN 1091 1100 MDS1/EVI1 mds1/evi1 NN 1101 1103 or or CC 1104 1107 the the DT 1108 1114 fusion fusion NN 1115 1122 protein protein NN 1123 1137 AML1/MDS1/EVI1 aml1/mds1/evi1 NN 1137 1138 , , , 1139 1141 to to TO 1142 1149 factors factor NNS 1150 1154 that that WDT 1155 1162 control control VBP 1163 1167 cell cell NN 1168 1183 differentiation differentiation NN 1184 1186 or or CC 1187 1191 cell cell NN 1192 1203 replication replication NN 1203 1204 . . . 1205 1208 The the DT 1209 1215 32Dcl3 32dcl3 NN 1216 1221 cells cell NNS 1222 1225 are be VBP 1226 1240 IL-3-dependent il-3-dependent JJ 1241 1244 for for IN 1245 1251 growth growth NN 1252 1255 and and CC 1256 1260 they they PRP 1261 1274 differentiate differentiate VBP 1275 1279 into into IN 1280 1292 granulocytes granulocyte NNS 1293 1297 when when WRB 1298 1305 exposed expose VBN 1306 1308 to to TO 1309 1314 G-CSF G-CSF NNP 1314 1315 . . . 1316 1320 They they PRP 1321 1324 are be VBP 1325 1341 growth-inhibited growth-inhibite VBN 1342 1344 by by IN 1345 1354 TGF-beta1 TGF-beta1 NNP 1354 1355 . . . 1356 1358 We we PRP 1359 1363 show show VBP 1364 1368 that that IN 1369 1376 whereas whereas IN 1377 1380 the the DT 1381 1391 expression expression NN 1392 1394 of of IN 1395 1404 MDS1/EVI1 MDS1/EVI1 NNP 1405 1408 has have VBZ 1409 1411 no no DT 1412 1418 effect effect NN 1419 1421 on on IN 1422 1434 granulocytic granulocytic JJ 1435 1450 differentiation differentiation NN 1451 1458 induced induce VBN 1459 1461 by by IN 1462 1467 G-CSF G-CSF NNP 1467 1468 , , , 1469 1479 expression expression NN 1480 1482 of of IN 1483 1497 AML1/MDS1/EVI1 aml1/mds1/evi1 NN 1498 1504 blocks block VBZ 1505 1520 differentiation differentiation NN 1521 1530 resulting result VBG 1531 1533 in in IN 1534 1538 cell cell NN 1539 1544 death death NN 1544 1545 . . . 1546 1550 This this DT 1551 1557 effect effect NN 1558 1560 is be VBZ 1561 1568 similar similar JJ 1569 1571 to to TO 1572 1576 that that DT 1577 1587 previously previously RB 1588 1597 described describe VBN 1598 1600 by by IN 1601 1607 others other NNS 1608 1611 for for IN 1612 1618 32Dcl3 32dcl3 NN 1619 1624 cells cell NNS 1625 1629 that that WDT 1630 1637 express express VBP 1638 1648 transgenic transgenic JJ 1649 1653 Evil Evil NNP 1653 1654 . . . 1655 1666 Furthermore furthermore RB 1666 1667 , , , 1668 1670 we we PRP 1671 1675 show show VBP 1676 1680 that that IN 1681 1688 whereas whereas IN 1689 1692 the the DT 1693 1703 expression expression NN 1704 1706 of of IN 1707 1710 the the DT 1711 1717 fusion fusion NN 1718 1725 protein protein NN 1726 1740 AML1/MDS1/EVI1 aml1/mds1/evi1 NN 1741 1751 completely completely RB 1752 1761 abrogates abrogate VBZ 1762 1765 the the DT 1766 1783 growth-inhibitory growth-inhibitory JJ 1784 1790 effect effect NN 1791 1793 of of IN 1794 1803 TGF-beta1 tgf-beta1 NN 1804 1807 and and CC 1808 1814 allows allow VBZ 1815 1821 32Dcl3 32dcl3 NN 1822 1827 cells cell NNS 1828 1830 to to TO 1831 1842 proliferate proliferate VB 1842 1843 , , , 1844 1854 expression expression NN 1855 1857 of of IN 1858 1861 the the DT 1862 1868 normal normal JJ 1869 1876 protein protein NN 1877 1886 MDS1/EVI1 mds1/evi1 NN 1887 1890 has have VBZ 1891 1894 the the DT 1895 1903 opposite opposite JJ 1904 1910 effect effect NN 1910 1911 , , , 1912 1915 and and CC 1916 1918 it it PRP 1919 1930 strengthens strengthen VBZ 1931 1934 the the DT 1935 1943 response response NN 1944 1946 of of IN 1947 1952 cells cell NNS 1953 1955 to to TO 1956 1959 the the DT 1960 1977 growth-inhibitory growth-inhibitory JJ 1978 1984 effect effect NN 1985 1987 of of IN 1988 1997 TGF-beta1 TGF-beta1 NNP 1997 1998 . . . 1999 2001 By by IN 2002 2007 using use VBG 2008 2011 the the DT 2012 2017 yeast yeast NN 2018 2028 two-hybrid two-hybrid JJ 2029 2035 system system NN 2035 2036 , , , 2037 2039 we we PRP 2040 2044 also also RB 2045 2049 show show VBP 2050 2054 that that IN 2055 2059 EVI1 evi1 NN 2060 2061 ( ( ( 2061 2070 contained contain VBN 2071 2073 in in IN 2074 2077 its its PRP$ 2078 2086 entirety entirety NN 2087 2089 in in IN 2090 2099 MDS1/EVI1 MDS1/EVI1 NNP 2100 2103 and and CC 2104 2118 AML1/MDS1/EVI1 AML1/MDS1/EVI1 NNP 2118 2119 ) ) ) 2120 2130 physically physically RB 2131 2140 interacts interact VBZ 2141 2145 with with IN 2146 2151 SMAD3 SMAD3 NNP 2151 2152 , , , 2153 2158 which which WDT 2159 2161 is be VBZ 2162 2164 an an DT 2165 2178 intracellular intracellular JJ 2179 2187 mediator mediator NN 2188 2190 of of IN 2191 2200 TGF-beta1 tgf-beta1 NN 2201 2210 signaling signaling NN 2210 2211 . . . 2212 2219 Finally finally RB 2219 2220 , , , 2221 2223 we we PRP 2224 2228 have have VBP 2229 2239 correlated correlate VBN 2240 2243 the the DT 2244 2252 response response NN 2253 2255 of of IN 2256 2259 the the DT 2260 2265 cells cell NNS 2266 2268 to to TO 2269 2274 G-CSF G-CSF NNP 2275 2277 or or CC 2278 2287 TGF-beta1 TGF-beta1 NNP 2288 2292 with with IN 2293 2296 the the DT 2297 2304 ability ability NN 2305 2307 of of IN 2308 2311 the the DT 2312 2318 normal normal JJ 2319 2322 and and CC 2323 2329 fusion fusion NN 2330 2338 proteins protein NNS 2339 2341 to to TO 2342 2350 activate activate VB 2351 2353 or or CC 2354 2361 repress repress VB 2362 2371 promoters promoter NNS 2372 2377 which which WDT 2378 2382 they they PRP 2383 2386 can can MD 2387 2395 directly directly RB 2396 2404 regulate regulate VB 2405 2407 by by IN 2408 2415 binding bind VBG 2416 2418 to to TO 2419 2422 the the DT 2423 2431 promoter promoter NN 2432 2436 site site NN 2436 2437 . . . 2438 2440 We we PRP 2441 2448 propose propose VBP 2449 2453 that that IN 2454 2463 mutations mutation NNS 2464 2466 of of IN 2467 2476 MDS1/EVI1 mds1/evi1 NN 2477 2483 either either CC 2484 2486 by by IN 2487 2491 gene gene NN 2492 2502 truncation truncation NN 2503 2512 resulting result VBG 2513 2515 in in IN 2516 2519 the the DT 2520 2533 transcription transcription NN 2534 2543 repressor repressor NN 2544 2548 EVI1 evi1 NN 2549 2551 or or CC 2552 2554 by by IN 2555 2559 gene gene NN 2560 2566 fusion fusion NN 2567 2569 to to TO 2570 2574 AML1 aml1 NN 2575 2579 lead lead VBP 2580 2582 to to TO 2583 2585 an an DT 2586 2593 altered altered JJ 2594 2602 cellular cellular JJ 2603 2611 response response NN 2612 2614 to to TO 2615 2621 growth growth NN 2622 2625 and and CC 2626 2641 differentiation differentiation NN 2642 2649 factors factor NNS 2650 2654 that that WDT 2655 2660 could could MD 2661 2667 result result VB 2668 2670 in in IN 2671 2679 leukemic leukemic JJ 2680 2694 transformation transformation NN 2694 2695 . . . 2696 2699 The the DT 2700 2709 different different JJ 2710 2718 response response NN 2719 2721 of of IN 2722 2729 myeloid myeloid JJ 2730 2735 cells cell NNS 2736 2747 ectopically ectopically RB 2748 2758 expressing express VBG 2759 2762 the the DT 2763 2769 normal normal JJ 2770 2772 or or CC 2773 2776 the the DT 2777 2783 fusion fusion NN 2784 2791 protein protein NN 2792 2794 to to TO 2795 2800 G-CSF G-CSF NNP 2801 2804 and and CC 2805 2814 TGF-beta1 TGF-beta1 NNP 2815 2820 could could MD 2821 2827 depend depend VB 2828 2830 on on IN 2831 2834 the the DT 2835 2844 different different JJ 2845 2860 transactivation transactivation NN 2861 2871 properties property NNS 2872 2874 of of IN 2875 2880 these these DT 2881 2889 proteins protein NNS 2890 2899 resulting result VBG 2900 2902 in in IN 2903 2912 divergent divergent JJ 2913 2923 expression expression NN 2924 2926 of of IN 2927 2937 downstream downstream JJ 2938 2943 genes gene NNS 2944 2953 regulated regulate VBN 2954 2956 by by IN 2957 2960 the the DT 2961 2964 two two CD 2965 2973 proteins protein NNS 2973 2974 . . .