0 19 Fludarabine-induced fludarabine-induced JJ 20 37 immunosuppression immunosuppression NN 38 40 is be VBZ 41 51 associated associate VBN 52 56 with with IN 57 67 inhibition inhibition NN 68 70 of of IN 71 76 STAT1 stat1 NN 77 86 signaling signaling NN 86 87 . . . 89 100 Fludarabine Fludarabine NNP 101 103 is be VBZ 104 105 a a DT 106 116 nucleoside nucleoside NN 117 123 analog analog NN 124 128 used use VBN 129 131 in in IN 132 135 the the DT 136 145 treatment treatment NN 146 148 of of IN 149 160 hematologic hematologic JJ 161 173 malignancies malignancy NNS 174 178 that that WDT 179 182 can can MD 183 189 induce induce VB 190 196 severe severe JJ 197 200 and and CC 201 210 prolonged prolonged JJ 211 228 immunosuppression immunosuppression NN 228 229 . . . 230 238 Although although IN 239 241 it it PRP 242 245 can can MD 246 248 be be VB 249 261 incorporated incorporate VBN 262 266 into into IN 267 270 the the DT 271 274 DNA dna NN 275 277 of of IN 278 286 dividing divide VBG 287 292 cells cell NNS 292 293 , , , 294 305 fludarabine fludarabine NN 306 308 is be VBZ 309 313 also also RB 314 315 a a DT 316 322 potent potent JJ 323 332 inhibitor inhibitor NN 333 335 of of IN 336 341 cells cell NNS 342 346 with with IN 347 348 a a DT 349 352 low low JJ 353 359 growth growth NN 360 368 fraction fraction NN 368 369 , , , 370 374 thus thus RB 375 377 it it PRP 378 382 must must MD 383 387 have have VB 388 393 other other JJ 394 404 mechanisms mechanism NNS 405 407 of of IN 408 414 action action NN 414 415 . . . 416 421 STAT1 STAT1 NNP 421 422 , , , 423 428 which which WDT 429 431 is be VBZ 432 441 activated activate VBN 442 444 in in IN 445 453 response response NN 454 456 to to TO 457 461 many many JJ 462 483 lymphocyte-activating lymphocyte-activating JJ 484 493 cytokines cytokine NNS 494 503 including include VBG 504 507 the the DT 508 519 interferons interferon NNS 519 520 , , , 521 523 is be VBZ 524 533 essential essential JJ 534 537 for for IN 538 551 cell-mediated cell-mediated JJ 552 560 immunity immunity NN 560 561 , , , 562 564 as as IN 565 568 the the DT 569 576 absence absence NN 577 579 of of IN 580 584 this this DT 585 592 protein protein NN 593 595 is be VBZ 596 606 associated associate VBN 607 611 with with IN 612 621 prominent prominent JJ 622 629 defects defect NNS 630 632 in in IN 633 636 the the DT 637 644 ability ability NN 645 647 to to TO 648 655 control control VB 656 661 viral viral JJ 662 672 infections infection NNS 672 673 . . . 674 678 Here here RB 679 681 we we PRP 682 686 show show VBP 687 691 that that IN 692 703 fludarabine fludarabine NN 703 704 , , , 705 708 but but CC 709 712 not not RB 713 716 the the DT 717 734 immunosuppressant immunosuppressant JJ 735 747 cyclosporine cyclosporine NN 748 749 A A NNP 749 750 , , , 751 759 inhibits inhibit VBZ 760 763 the the DT 764 780 cytokine-induced cytokine-induced JJ 781 791 activation activation NN 792 794 of of IN 795 800 STAT1 STAT1 NNP 801 804 and and CC 805 820 STAT1-dependent stat1-dependent JJ 821 825 gene gene NN 826 839 transcription transcription NN 840 842 in in IN 843 849 normal normal JJ 850 857 resting rest VBG 858 860 or or CC 861 870 activated activate VBN 871 882 lymphocytes lymphocyte NNS 882 883 . . . 884 895 Fludarabine Fludarabine NNP 896 902 caused cause VBD 903 904 a a DT 905 913 specific specific JJ 914 923 depletion depletion NN 924 926 of of IN 927 932 STAT1 stat1 NN 933 940 protein protein NN 941 942 ( ( ( 942 945 and and CC 946 950 mRNA mrna NN 950 951 ) ) ) 952 955 but but CC 956 959 not not RB 960 962 of of IN 963 968 other other JJ 969 974 STATs stat NNS 974 975 . . . 976 980 This this DT 981 985 loss loss NN 986 988 of of IN 989 994 STAT1 STAT1 NNP 995 998 was be VBD 999 1003 also also RB 1004 1008 seen see VBN 1009 1011 in in IN 1012 1017 cells cell NNS 1018 1022 from from IN 1023 1031 patients patient NNS 1032 1039 treated treat VBN 1040 1044 with with IN 1045 1056 fludarabine fludarabine NN 1057 1059 in in FW 1060 1064 vivo vivo FW 1064 1065 . . . 1066 1071 Brief brief JJ 1072 1080 exposure exposure NN 1081 1083 to to TO 1084 1095 fludarabine fludarabine NN 1096 1099 led lead VBD 1100 1102 to to TO 1103 1104 a a DT 1105 1114 sustained sustained JJ 1115 1119 loss loss NN 1120 1122 of of IN 1123 1128 STAT1 STAT1 NNP 1128 1129 , , , 1130 1139 analogous analogous JJ 1140 1142 to to TO 1143 1146 the the DT 1147 1156 prolonged prolonged JJ 1157 1163 period period NN 1164 1166 of of IN 1167 1184 immunosuppression immunosuppression NN 1185 1192 induced induce VBN 1193 1195 by by IN 1196 1204 exposure exposure NN 1205 1207 to to TO 1208 1211 the the DT 1212 1216 drug drug NN 1217 1219 in in FW 1220 1224 vivo vivo FW 1224 1225 . . . 1226 1230 Thus thus RB 1230 1231 , , , 1232 1237 STAT1 STAT1 NNP 1238 1241 may may MD 1242 1244 be be VB 1245 1246 a a DT 1247 1253 useful useful JJ 1254 1260 target target NN 1261 1263 in in IN 1264 1267 the the DT 1268 1279 development development NN 1280 1282 of of IN 1283 1286 new new JJ 1287 1304 immunosuppressive immunosuppressive JJ 1305 1308 and and CC 1309 1323 antineoplastic antineoplastic JJ 1324 1330 agents agent NNS 1330 1331 . . .