0 4 Cell cell NN 5 13 specific specific JJ 14 24 expression expression NN 25 27 of of IN 28 33 human human JJ 34 40 Bruton Bruton NNP 40 42 ’s 's POS 43 61 agammaglobulinemia agammaglobulinemia NN 62 70 tyrosine tyrosine NN 71 77 kinase kinase NNP 78 82 gene gene NN 83 84 ( ( ( 84 87 Btk Btk NNP 87 88 ) ) ) 89 91 is be VBZ 92 101 regulated regulate VBN 102 104 by by IN 105 109 Sp1- Sp1- NNP 110 113 and and CC 114 131 Spi-1/PU.1-family Spi-1/PU.1-family NNP 132 139 members member NNS 139 140 . . . 142 148 Bruton Bruton NNP 148 150 ’s 's POS 151 169 agammaglobulinemia agammaglobulinemia NN 170 178 tyrosine tyrosine NN 179 185 kinase kinase NNP 186 187 ( ( ( 187 190 Btk Btk NNP 190 191 ) ) ) 192 194 is be VBZ 195 196 a a DT 197 208 cytoplasmic cytoplasmic JJ 209 217 tyrosine tyrosine NN 218 224 kinase kinase NNP 225 233 involved involve VBN 234 236 in in IN 237 240 the the DT 241 246 human human JJ 247 254 disease disease NN 255 263 X-linked x-linked JJ 264 282 agammaglobulinemia agammaglobulinemia NN 283 284 ( ( ( 284 287 XLA XLA NNP 287 288 ) ) ) 288 289 . . . 290 293 The the DT 294 298 gene gene NN 299 301 is be VBZ 302 311 expressed express VBN 312 314 in in IN 315 318 all all DT 319 332 hematopoietic hematopoietic JJ 333 338 cells cell NNS 339 343 with with IN 344 347 the the DT 348 357 exception exception NN 358 360 of of IN 361 368 T-cells T-cell NNP 369 372 and and CC 373 379 plasma plasma NN 380 385 cells cell NNS 385 386 . . . 387 390 For for IN 391 395 this this DT 396 406 expression expression NN 407 414 pattern pattern NN 415 418 the the DT 419 424 first first JJ 425 428 280 280 CD 429 431 bp bp NN 432 440 upstream upstream RB 441 443 of of IN 444 447 the the DT 448 453 major major JJ 454 469 transcriptional transcriptional JJ 470 475 start start NN 476 480 site site NN 481 486 seems seem VBZ 487 489 to to TO 490 492 be be VB 493 503 sufficient sufficient JJ 503 504 . . . 505 507 In in FW 508 513 vitro vitro FW 514 526 footprinting footprinting NN 527 535 analysis analysis NN 536 542 within within IN 543 547 this this DT 548 552 part part NN 553 555 of of IN 556 559 the the DT 560 568 promoter promoter NN 569 577 revealed reveal VBD 578 581 two two CD 582 585 Sp1 sp1 NN 586 593 binding binding NN 594 599 sites site NNS 600 602 as as RB 603 607 well well RB 608 610 as as IN 611 612 a a DT 613 619 PU-box pu-box NN 619 620 . . . 621 624 The the DT 625 638 transcription transcription NN 639 645 factor factor NN 646 656 Spi-1/PU.1 spi-1/pu.1 NN 657 659 as as RB 660 664 well well RB 665 667 as as IN 668 671 the the DT 672 679 closely closely RB 680 687 related related JJ 688 694 factor factor NN 695 700 Spi-B spi-b NN 701 706 bound bind VBD 707 709 to to TO 710 713 the the DT 714 720 PU-box PU-box NNP 721 723 in in IN 724 731 B-cells B-cell NNP 731 732 . . . 733 735 In in IN 736 739 the the DT 740 755 erythroleukemia erythroleukemia NN 756 760 cell cell NN 761 765 line line NN 766 770 K562 k562 NN 770 771 , , , 772 775 due due IN 776 778 to to TO 779 782 the the DT 783 790 absence absence NN 791 793 of of IN 794 799 Spi-B Spi-B NNP 799 800 , , , 801 805 only only RB 806 810 PU.1 pu.1 NN 811 816 bound bind VBD 817 819 to to TO 820 823 the the DT 824 827 Btk Btk NNP 828 836 promoter promoter NN 836 837 . . . 838 846 Mutation mutation NN 847 849 of of IN 850 856 either either DT 857 861 site site NN 862 869 reduced reduce VBD 870 873 the the DT 874 884 expression expression NN 885 887 in in IN 888 897 transient transient JJ 898 910 transfection transfection NN 911 922 experiments experiment NNS 922 923 . . . 924 931 However however RB 931 932 , , , 933 941 mutation mutation NN 942 944 of of IN 945 948 the the DT 949 951 PU PU NNP 952 955 box box NN 956 959 had have VBD 960 962 no no DT 963 969 effect effect NN 970 972 in in IN 973 976 the the DT 977 983 T-cell t-cell NN 984 988 line line NN 989 995 Jurkat Jurkat NNP 995 996 , , , 997 1002 where where WRB 1003 1007 none none NN 1008 1010 of of IN 1011 1014 the the DT 1015 1020 Spi-1 spi-1 NN 1021 1027 family family NN 1028 1035 members member NNS 1036 1038 is be VBZ 1039 1048 expressed express VBN 1048 1049 . . . 1050 1052 In in IN 1053 1061 addition addition NN 1062 1067 Spi-B spi-b NN 1068 1070 as as RB 1071 1075 well well RB 1076 1078 as as IN 1079 1083 PU.1 PU.1 NNP 1084 1088 were be VBD 1089 1093 able able JJ 1094 1096 to to TO 1097 1110 transactivate transactivate VB 1111 1114 Btk Btk NNP 1115 1125 expression expression NN 1125 1126 . . . 1127 1129 In in IN 1130 1135 fetal fetal JJ 1136 1141 liver liver NN 1142 1144 of of IN 1145 1152 PU.1-/- pu.1-/- JJ 1153 1157 mice mouse NNS 1157 1158 , , , 1159 1164 which which WDT 1165 1169 lack lack VBP 1170 1178 lymphoid lymphoid JJ 1179 1182 and and CC 1183 1190 myeloid myeloid JJ 1191 1196 cells cell NNS 1196 1197 , , , 1198 1208 expression expression NN 1209 1211 of of IN 1212 1215 Btk Btk NNP 1216 1219 was be VBD 1220 1227 reduced reduce VBN 1228 1232 two- two- CD 1233 1235 to to TO 1236 1245 threefold threefold RB 1246 1249 but but CC 1250 1253 not not RB 1254 1263 abolished abolish VBN 1263 1264 . . . 1265 1277 Collectively collectively RB 1278 1282 this this DT 1283 1288 study study NN 1289 1294 shows show VBZ 1295 1299 that that IN 1300 1310 expression expression NN 1311 1313 of of IN 1314 1317 the the DT 1318 1321 Btk Btk NNP 1322 1326 gene gene NN 1327 1329 is be VBZ 1330 1339 regulated regulate VBN 1340 1342 by by IN 1343 1346 the the DT 1347 1355 combined combined JJ 1356 1362 action action NN 1363 1365 of of IN 1366 1370 Sp1- Sp1- NNP 1371 1374 and and CC 1375 1386 PU.1-family PU.1-family NNP 1387 1394 members member NNS 1394 1395 . . .