;PMID: 9305595 ;source_file_1221.mrg ;Release 0.9 of PennBioIE ;Funded by NSF ITR EIA-0205448 ;0)section:[e:0..31] = [t:0..31] ;1)sentence:[e:36..145] = [t:36..145] ;2)section:[e:149..255] = [t:149..255] ;3)section:[e:259..345] = [t:259..345] ;4)sentence:[e:349..506] = [t:349..506] ;5)sentence:[e:508..816] = [t:508..816] ;6)sentence:[e:817..1020] = [t:817..1020] ;7)sentence:[e:1021..1214] = [t:1021..1214] ;8)sentence:[e:1215..1307] = [t:1215..1307] ;9)sentence:[e:1308..1547] = [t:1308..1547] ;10)sentence:[e:1548..1690] = [t:1548..1690] ;11)sentence:[e:1691..1740] = [t:1691..1740] ;12)sentence:[e:1742..1954] = [t:1742..1954] ;13)section:[e:1958..2002] = [t:1958..2002] ;section 0 Span:0..31 ;Leukemia 1997 Sep;11(9):1442-6 (SEC (FRAG (IN:[0..8] Leukemia) (CD:[10..14] 1997) (CC:[15..22] Sep;11-LRB-) (CD:[22..23] 9) (-RRB-:[23..24] -RRB-) (CD:[24..29] :1442) (::[29..30] -) (CD:[30..31] 6))) ;sentence 1 Span:36..145 ;Tandem duplications of the FLT3 receptor gene are associated with leukemic ;transformation of myelodysplasia. ;[36..55]:variation-type:"Tandem duplications" ;[63..76]:gene-rna:"FLT3 receptor" ;[130..144]:malignancy:"myelodysplasia" (SENT (S-HLN (NP-SBJ-1 (NP (JJ:[36..42] Tandem) (NNS:[43..55] duplications)) (PP (IN:[56..58] of) (NP (DT:[59..62] the) (NML (NN:[63..67] FLT3) (NN:[68..76] receptor)) (NN:[77..81] gene)))) (VP (VBP:[82..85] are) (VP (VBN:[86..96] associated) (NP-1 (-NONE-:[96..96] *)) (PP-CLR (IN:[97..101] with) (NP (NP (JJ:[102..110] leukemic) (NN:[112..126] transformation)) (PP (IN:[127..129] of) (NP (NN:[130..144] myelodysplasia))))))) (.:[144..145] .))) ;section 2 Span:149..255 ;Horiike S, Yokota S, Nakao M, Iwai T, Sasai Y, Kaneko H, Taniwaki M, Kashima ;K, Fujii H, Abe T, Misawa S. (SEC (FRAG (NNP:[149..156] Horiike) (NNP:[157..159] S,) (NNP:[160..166] Yokota) (NNP:[167..169] S,) (NNP:[170..175] Nakao) (NNP:[176..178] M,) (NNP:[179..183] Iwai) (NNP:[184..185] T) (,:[185..186] ,) (NNP:[187..192] Sasai) (NNP:[193..194] Y) (,:[194..195] ,) (NNP:[196..202] Kaneko) (NNP:[203..204] H) (,:[204..205] ,) (NNP:[206..214] Taniwaki) (NNP:[215..217] M,) (NNP:[218..225] Kashima) (NNP:[226..227] K) (,:[227..228] ,) (NNP:[230..235] Fujii) (NNP:[236..237] H) (,:[237..238] ,) (NNP:[239..242] Abe) (NNP:[243..244] T) (,:[244..245] ,) (NNP:[246..252] Misawa) (NNP:[253..255] S.))) ;section 3 Span:259..345 ;Department of Internal Medicine III, Kyoto Prefectural University of ;Medicine, Japan. (SEC (FRAG (NNP:[259..269] Department) (IN:[270..272] of) (NNP:[273..281] Internal) (NNP:[282..290] Medicine) (NNP:[291..294] III) (,:[294..295] ,) (NNP:[296..301] Kyoto) (NNP:[302..313] Prefectural) (NNP:[314..324] University) (IN:[325..327] of) (NNP:[328..336] Medicine) (,:[336..337] ,) (NNP:[339..344] Japan) (.:[344..345] .))) ;sentence 4 Span:349..506 ;We recently reported an internal tandem duplication of the human flt3 ;receptor gene (FLT3) as a somatic mutation in 17% of acute myelogenous ;leukemia (AML). ;[382..400]:variation-type:"tandem duplication" ;[414..427]:gene-rna:"flt3 receptor" ;[435..439]:gene-rna:"FLT3" ;[454..462]:variation-event:"mutation" ;[473..499]:malignancy:"acute myelogenous leukemia" ;[501..504]:malignancy:"AML" (SENT (S (NP-SBJ (PRP:[349..351] We)) (ADVP-TMP (RB:[352..360] recently)) (VP (VBD:[361..369] reported) (NP (NP (DT:[370..372] an) (JJ:[373..381] internal) (JJ:[382..388] tandem) (NN:[389..400] duplication)) (PP (IN:[401..403] of) (NP (NP (DT:[404..407] the) (JJ:[408..413] human) (NML (NN:[414..418] flt3) (NN:[419..427] receptor)) (NN:[429..433] gene)) (NP (-LRB-:[434..435] -LRB-) (NN:[435..439] FLT3) (-RRB-:[439..440] -RRB-))))) (PP (IN:[441..443] as) (NP (DT:[444..445] a) (JJ:[446..453] somatic) (NN:[454..462] mutation))) (PP (IN:[463..465] in) (NP (NP (CD:[466..468] 17) (NN:[468..469] %)) (PP (IN:[470..472] of) (NP (NP (JJ:[473..478] acute) (JJ:[479..490] myelogenous) (NN:[491..499] leukemia)) (NP (-LRB-:[500..501] -LRB-) (NN:[501..504] AML) (-RRB-:[504..505] -RRB-))))))) (.:[505..506] .))) ;sentence 5 Span:508..816 ;The present study revealed the duplication at the juxtamembrane and the first ; tyrosine kinase domains of FLT3 in seven of 92 (8%) patients with ;myelodysplastic syndrome (MDS) and AML with trilineage myelodysplasia ;(AML/TMDS), the diseases which may represent neoplastic changes of ;pluripotent stem cells. ;[539..550]:variation-type:"duplication" ;[614..618]:gene-rna:"FLT3" ;[654..678]:malignancy:"myelodysplastic syndrome" ;[680..683]:malignancy:"MDS" ;[689..692]:malignancy:"AML" ;[698..723]:malignancy:"trilineage myelodysplasia" ;[726..729]:malignancy:"AML" ;[730..734]:malignancy:"TMDS" (SENT (S (NP-SBJ (DT:[508..511] The) (JJ:[512..519] present) (NN:[520..525] study)) (VP (VBD:[526..534] revealed) (NP (DT:[535..538] the) (NN:[539..550] duplication)) (PP-LOC (IN:[551..553] at) (NP (NP (NP (DT:[554..557] the) (NN:[558..571] juxtamembrane) (NML-1 (-NONE-:[571..571] *P*))) (CC:[572..575] and) (NP (DT:[576..579] the) (JJ:[580..585] first) (NML (NN:[587..595] tyrosine) (NN:[596..602] kinase)) (NML-1 (NNS:[603..610] domains)))) (PP (IN:[611..613] of) (NP (NP (NN:[614..618] FLT3)) (PP-LOC (IN:[619..621] in) (NP (NP (CD:[622..627] seven)) (PP (IN:[628..630] of) (NP (NP (CD:[631..633] 92) (PRN (-LRB-:[634..635] -LRB-) (NP (CD:[635..636] 8) (NN:[636..637] %)) (-RRB-:[637..638] -RRB-)) (NNS:[639..647] patients)) (PP (IN:[648..652] with) (NP (NP (NP (NP (JJ:[654..669] myelodysplastic) (NN:[670..678] syndrome)) (NP (-LRB-:[679..680] -LRB-) (NN:[680..683] MDS) (-RRB-:[683..684] -RRB-))) (CC:[685..688] and) (NP (NP (NP (NN:[689..692] AML)) (PP (IN:[693..697] with) (NP (NN:[698..708] trilineage) (NN:[709..723] myelodysplasia)))) (NP (-LRB-:[725..726] -LRB-) (NN:[726..729] AML) (PP (SYM:[729..730] /) (NP (NN:[730..734] TMDS))) (-RRB-:[734..735] -RRB-)))) (,:[735..736] ,) (NP (NP (DT:[737..740] the) (NNS:[741..749] diseases)) (SBAR (WHNP-2 (WDT:[750..755] which)) (S (NP-SBJ-2 (-NONE-:[755..755] *T*)) (VP (MD:[756..759] may) (VP (VB:[760..769] represent) (NP (NP (JJ:[770..780] neoplastic) (NNS:[781..788] changes)) (PP (IN:[789..791] of) (NP (JJ:[792..803] pluripotent) (NN:[805..809] stem) (NNS:[810..815] cells)))))))))))))))))))) (.:[815..816] .))) ;sentence 6 Span:817..1020 ;A tandem duplication of exon 11 of FLT3 was harbored by two of 58 (3%) ;patients with MDS and five of 34 (15%) with overt leukemia, including ;MDS-derived leukemia, AML/TMDS and therapy-related leukemia. ;[819..837]:variation-type:"tandem duplication" ;[841..848]:variation-location:"exon 11" ;[852..856]:gene-rna:"FLT3" ;[903..906]:malignancy:"MDS" ;[933..947]:malignancy:"overt leukemia" ;[960..980]:malignancy:"MDS-derived leukemia" ;[960..963]:malignancy:"MDS" ;[982..985]:malignancy:"AML" ;[986..990]:malignancy:"TMDS" ;[995..1019]:malignancy:"therapy-related leukemia" (SENT (S (NP-SBJ-1 (NP (DT:[817..818] A) (JJ:[819..825] tandem) (NN:[826..837] duplication)) (PP (IN:[838..840] of) (NP (NP (NN:[841..845] exon) (CD:[846..848] 11)) (PP (IN:[849..851] of) (NP (NN:[852..856] FLT3)))))) (VP (VBD:[857..860] was) (VP (VBN:[861..869] harbored) (NP-1 (-NONE-:[869..869] *)) (PP (IN:[870..872] by) (NP-LGS (NP (NP (CD:[873..876] two)) (PP (IN:[877..879] of) (NP (NP (CD:[880..882] 58) (PRN (-LRB-:[884..885] -LRB-) (NP (CD:[885..886] 3) (NN:[886..887] %)) (-RRB-:[887..888] -RRB-)) (NNS:[889..897] patients)) (PP (IN:[898..902] with) (NP (NN:[903..906] MDS)))))) (CC:[907..910] and) (NP (NP (CD:[911..915] five)) (PP (IN:[916..918] of) (NP (NP (CD:[919..921] 34) (PRN (-LRB-:[922..923] -LRB-) (NP (CD:[923..925] 15) (NN:[925..926] %)) (-RRB-:[926..927] -RRB-))) (PP (IN:[928..932] with) (NP (NP (JJ:[933..938] overt) (NN:[939..947] leukemia)) (,:[947..948] ,) (PP (VBG:[949..958] including) (NP (NP (ADJP (NN:[960..963] MDS) (HYPH:[963..964] -) (VBN:[964..971] derived)) (NN:[972..980] leukemia)) (,:[980..981] ,) (NP (NN:[982..985] AML) (SYM:[985..986] /) (NN:[986..990] TMDS)) (CC:[991..994] and) (NP (ADJP (NN:[995..1002] therapy) (HYPH:[1002..1003] -) (VBN:[1003..1010] related)) (NN:[1011..1019] leukemia))))))))))))) (.:[1019..1020] .))) ;sentence 7 Span:1021..1214 ;Although the duplicated regions varied within exon 11 in each case, they ;occurred in-frame, and altered mRNA expressions were demonstrated by ;reverse-transcription polymerase chain reaction. ;[1068..1075]:variation-location:"exon 11" ;[1188..1198]:gene-protein:"polymerase" (SENT (S (S (SBAR-ADV (IN:[1021..1029] Although) (S (NP-SBJ (DT:[1030..1033] the) (VBN:[1035..1045] duplicated) (NNS:[1046..1053] regions)) (VP (VBD:[1054..1060] varied) (PP (IN:[1061..1067] within) (NP (NN:[1068..1072] exon) (CD:[1073..1075] 11))) (PP (IN:[1076..1078] in) (NP (DT:[1079..1083] each) (NN:[1084..1088] case)))))) (,:[1088..1089] ,) (NP-SBJ (PRP:[1090..1094] they)) (VP (VBD:[1095..1103] occurred) (ADVP-LOC (IN:[1104..1106] in) (HYPH:[1106..1107] -) (NN:[1107..1112] frame)))) (,:[1112..1113] ,) (CC:[1115..1118] and) (S (NP-SBJ-1 (VBN:[1119..1126] altered) (NN:[1127..1131] mRNA) (NNS:[1132..1143] expressions)) (VP (VBD:[1144..1148] were) (VP (VBN:[1149..1161] demonstrated) (NP-1 (-NONE-:[1161..1161] *)) (PP-MNR (IN:[1162..1164] by) (NP (NML (JJ:[1165..1172] reverse) (HYPH:[1172..1173] -) (NN:[1173..1186] transcription)) (NN:[1188..1198] polymerase) (NN:[1199..1204] chain) (NN:[1205..1213] reaction)))))) (.:[1213..1214] .))) ;sentence 8 Span:1215..1307 ;Two cases of MDS with a FLT3 duplication transformed to overt leukemia ;within a few months. ;[1228..1231]:malignancy:"MDS" ;[1239..1243]:gene-rna:"FLT3" ;[1272..1286]:malignancy:"overt leukemia" (SENT (S (NP-SBJ (NP (CD:[1215..1218] Two) (NNS:[1219..1224] cases)) (PP (IN:[1225..1227] of) (NP (NP (NN:[1228..1231] MDS)) (PP (IN:[1232..1236] with) (NP (DT:[1237..1238] a) (NN:[1239..1243] FLT3) (NN:[1244..1255] duplication)))))) (VP (VBD:[1256..1267] transformed) (PP (TO:[1269..1271] to) (NP (JJ:[1272..1277] overt) (NN:[1278..1286] leukemia))) (PP-TMP (IN:[1287..1293] within) (NP (DT:[1294..1295] a) (JJ:[1296..1299] few) (NNS:[1300..1306] months)))) (.:[1306..1307] .))) ;sentence 9 Span:1308..1547 ;Longitudinal analyses in two other patients with leukemia revealed that the ;duplication was a late genetic event during the disease course; one of whom ;showed two independent duplications of FLT3 at the terminal ;therapy-resistant phase. ;[1358..1366]:malignancy:"leukemia" ;[1385..1396]:variation-type:"duplication" ;[1485..1497]:variation-type:"duplications" ;[1502..1506]:gene-rna:"FLT3" (SENT (S (NP-SBJ (NP (JJ:[1308..1320] Longitudinal) (NNS:[1321..1329] analyses)) (PP (IN:[1330..1332] in) (NP (NP (CD:[1333..1336] two) (JJ:[1337..1342] other) (NNS:[1344..1352] patients)) (PP (IN:[1353..1357] with) (NP (NN:[1358..1366] leukemia)))))) (VP (VBD:[1367..1375] revealed) (SBAR (IN:[1376..1380] that) (S (NP-SBJ (DT:[1381..1384] the) (NN:[1385..1396] duplication)) (VP (VBD:[1397..1400] was) (NP-PRD (NP (NP (DT:[1401..1402] a) (JJ:[1403..1407] late) (JJ:[1408..1415] genetic) (NN:[1416..1421] event)) (PP-TMP (IN:[1423..1429] during) (NP (DT:[1430..1433] the) (NN:[1434..1441] disease) (NN:[1442..1448] course)))) (::[1448..1449] ;) (SBAR (WHNP-1 (NP (CD:[1450..1453] one)) (WHPP (IN:[1454..1456] of) (WHNP (WP:[1457..1461] whom)))) (S (NP-SBJ-1 (-NONE-:[1461..1461] *T*)) (VP (VBD:[1462..1468] showed) (NP (NP (CD:[1469..1472] two) (JJ:[1473..1484] independent) (NNS:[1485..1497] duplications)) (PP (IN:[1498..1500] of) (NP (NN:[1502..1506] FLT3)))) (PP (IN:[1507..1509] at) (NP (DT:[1510..1513] the) (JJ:[1514..1522] terminal) (ADJP (NN:[1523..1530] therapy) (HYPH:[1530..1531] -) (JJ:[1531..1540] resistant)) (NN:[1541..1546] phase))))))))))) (.:[1546..1547] .))) ;sentence 10 Span:1548..1690 ;Of seven patients with the FLT3 duplication, six had abnormal karyotypes, ;and four harbored a point mutation of the N-RAS and/or TP53 genes. ;[1575..1579]:gene-rna:"FLT3" ;[1581..1592]:variation-type:"duplication" ;[1643..1657]:variation-type:"point mutation" ;[1666..1671]:gene-rna:"N-RAS" ;[1679..1683]:gene-rna:"TP53" (SENT (S (PP-TPC-1 (IN:[1548..1550] Of) (NP (NP (CD:[1551..1556] seven) (NNS:[1557..1565] patients)) (PP (IN:[1566..1570] with) (NP (DT:[1571..1574] the) (NN:[1575..1579] FLT3) (NN:[1581..1592] duplication))))) (,:[1592..1593] ,) (S (NP-SBJ (NP (CD:[1594..1597] six)) (PP-1 (-NONE-:[1597..1597] *T*))) (VP (VBD:[1598..1601] had) (NP (JJ:[1602..1610] abnormal) (NNS:[1611..1621] karyotypes)))) (,:[1621..1622] ,) (CC:[1623..1626] and) (S (NP-SBJ (NP (CD:[1627..1631] four)) (PP-1 (-NONE-:[1631..1631] *T*))) (VP (VBD:[1632..1640] harbored) (NP (NP (DT:[1641..1642] a) (NN:[1643..1648] point) (NN:[1649..1657] mutation)) (PP (IN:[1658..1660] of) (NP (DT:[1662..1665] the) (NML (NML (NN:[1666..1671] N-RAS) (NML-2 (-NONE-:[1671..1671] *P*))) (CC:[1672..1678] and/or) (NML (NN:[1679..1683] TP53) (NML-2 (NNS:[1684..1689] genes))))))))) (.:[1689..1690] .))) ;sentence 11 Span:1691..1740 ;Patients with FLT3 mutations have poor prognoses. ;[1705..1709]:gene-rna:"FLT3" (SENT (S (NP-SBJ (NP (NNS:[1691..1699] Patients)) (PP (IN:[1700..1704] with) (NP (NN:[1705..1709] FLT3) (NNS:[1710..1719] mutations)))) (VP (VBP:[1720..1724] have) (NP (JJ:[1725..1729] poor) (NNS:[1730..1739] prognoses))) (.:[1739..1740] .))) ;sentence 12 Span:1742..1954 ;This study uncovered the fact that the accumulation of genetic events, ;including FLT3 duplication, correlates with leukemic transformation from ;antecedent myelodysplasia and with subsequent disease progression. ;[1824..1828]:gene-rna:"FLT3" ;[1829..1840]:variation-type:"duplication" ;[1899..1913]:malignancy:"myelodysplasia" (SENT (S (NP-SBJ (DT:[1742..1746] This) (NN:[1747..1752] study)) (VP (VBD:[1753..1762] uncovered) (NP (DT:[1763..1766] the) (NN:[1767..1771] fact) (SBAR (IN:[1772..1776] that) (S (NP-SBJ (NP (DT:[1777..1780] the) (NN:[1781..1793] accumulation)) (PP (IN:[1794..1796] of) (NP (NP (JJ:[1797..1804] genetic) (NNS:[1805..1811] events)) (,:[1811..1812] ,) (PP (VBG:[1813..1822] including) (NP (NN:[1824..1828] FLT3) (NN:[1829..1840] duplication)))))) (,:[1840..1841] ,) (VP (VBZ:[1842..1852] correlates) (PP-CLR (PP (IN:[1853..1857] with) (NP (NP (JJ:[1858..1866] leukemic) (NN:[1867..1881] transformation)) (PP (IN:[1882..1886] from) (NP (JJ:[1887..1897] antecedent) (NN:[1899..1913] myelodysplasia))))) (CC:[1914..1917] and) (PP (IN:[1918..1922] with) (NP (JJ:[1923..1933] subsequent) (NN:[1934..1941] disease) (NN:[1942..1953] progression))))))))) (.:[1953..1954] .))) ;section 13 Span:1958..2002 ;PMID: 9305595 [PubMed - indexed for MEDLINE] (SEC (FRAG (NNP:[1958..1962] PMID) (::[1962..1963] :) (CD:[1964..1971] 9305595) (NN:[1972..1973] -LSB-) (NNP:[1973..1979] PubMed) (::[1980..1981] -) (NN:[1982..1989] indexed) (IN:[1990..1993] for) (NNP:[1994..2002] MEDLINE-RSB-)))