0 7 HLA-DR- hla-dr- JJ 7 8 , , , 9 14 CD33+ cd33+ JJ 14 15 , , , 16 21 CD56+ cd56+ JJ 21 22 , , , 23 28 CD16- cd16- JJ 29 44 myeloid/natural myeloid/natural JJ 45 51 killer killer NN 52 56 cell cell NN 57 62 acute acute JJ 63 71 leukemia leukemia NN 71 72 : : : 73 74 a a DT 75 85 previously previously RB 86 98 unrecognized unrecognized JJ 99 103 form form NN 104 106 of of IN 107 112 acute acute JJ 113 121 leukemia leukemia NN 122 133 potentially potentially RB 134 146 misdiagnosed misdiagnose VBN 147 149 as as IN 150 173 French-American-British french-american-british JJ 174 179 acute acute JJ 180 187 myeloid myeloid JJ 188 199 leukemia-M3 leukemia-m3 NN 200 201 [ [ ( 201 204 see see VB 205 213 comments comment NNS 213 214 ] ] ) 216 218 We we PRP 219 223 have have VBP 224 234 identified identify VBN 235 238 and and CC 239 252 characterized characterize VBN 253 254 a a DT 255 265 previously previously RB 266 278 unrecognized unrecognized JJ 279 283 form form NN 284 286 of of IN 287 292 acute acute JJ 293 301 leukemia leukemia NN 302 306 that that WDT 307 313 shares share VBZ 314 322 features feature NNS 323 325 of of IN 326 330 both both CC 331 338 myeloid myeloid JJ 339 342 and and CC 343 350 natural natural JJ 351 357 killer killer NN 358 359 ( ( ( 359 361 NK NK NNP 361 362 ) ) ) 363 368 cells cell NNS 368 369 . . . 370 374 From from IN 375 376 a a DT 377 388 consecutive consecutive JJ 389 395 series series NN 396 398 of of IN 399 402 350 350 CD 403 408 cases case NNS 409 411 of of IN 412 417 adult adult JJ 418 420 de de FW 421 425 novo novo FW 426 431 acute acute JJ 432 439 myeloid myeloid JJ 440 448 leukemia leukemia NN 449 450 ( ( ( 450 453 AML AML NNP 453 454 ) ) ) 454 455 , , , 456 458 we we PRP 459 469 identified identify VBD 470 472 20 20 CD 473 478 cases case NNS 479 480 ( ( ( 480 481 6 6 CD 481 482 % % NN 482 483 ) ) ) 484 488 with with IN 489 490 a a DT 491 497 unique unique JJ 498 513 immunophenotype immunophenotype NN 513 514 : : : 515 520 CD33+ cd33+ JJ 520 521 , , , 522 527 CD56+ cd56+ JJ 527 528 , , , 529 535 CD11a+ cd11a+ JJ 535 536 , , , 537 543 CD13lo cd13lo NN 543 544 , , , 545 551 CD15lo cd15lo NN 551 552 , , , 553 560 CD34+/- cd34+/- JJ 560 561 , , , 562 569 HLA-DR- hla-dr- JJ 569 570 , , , 571 576 CD16- cd16- JJ 576 577 . . . 578 588 Multicolor multicolor JJ 589 593 flow flow NN 594 604 cytometric cytometric JJ 605 611 assays assay NNS 612 621 confirmed confirm VBD 622 625 the the DT 626 638 coexpression coexpression NN 639 641 of of IN 642 649 myeloid myeloid JJ 650 651 ( ( ( 651 655 CD33 CD33 NNP 655 656 , , , 657 661 CD13 CD13 NNP 661 662 , , , 663 667 CD15 CD15 NNP 667 668 ) ) ) 669 672 and and CC 673 675 NK NK NNP 676 691 cell-associated cell-associated JJ 692 693 ( ( ( 693 697 CD56 CD56 NNP 697 698 ) ) ) 699 707 antigens antigen NNS 708 710 in in IN 711 715 each each DT 716 720 case case NN 720 721 , , , 722 729 whereas whereas IN 730 737 reverse reverse JJ 738 751 transcription transcription NN 752 762 polymerase polymerase NN 763 768 chain chain NN 769 777 reaction reaction NN 778 779 ( ( ( 779 785 RT-PCR RT-PCR NNP 785 786 ) ) ) 787 793 assays assay NNS 794 803 confirmed confirm VBD 804 807 the the DT 808 816 identity identity NN 817 819 of of IN 820 824 CD56 CD56 NNP 825 826 ( ( ( 826 832 neural neural JJ 833 837 cell cell NN 838 846 adhesion adhesion NN 847 855 molecule molecule NN 855 856 ) ) ) 857 859 in in IN 860 868 leukemic leukemic JJ 869 875 blasts blast NNS 875 876 . . . 877 885 Although although IN 886 889 two two CD 890 895 cases case NNS 896 905 expressed express VBD 906 909 CD4 cd4 NN 909 910 , , , 911 913 no no DT 914 918 case case NN 919 928 expressed express VBD 929 932 CD2 cd2 NN 932 933 , , , 934 937 CD3 CD3 NNP 937 938 , , , 939 941 or or CC 942 945 CD8 cd8 NN 946 949 and and CC 950 952 no no DT 953 957 case case NN 958 964 showed show VBD 965 971 clonal clonal JJ 972 985 rearrangement rearrangement NN 986 988 of of IN 989 994 genes gene NNS 995 1003 encoding encode VBG 1004 1007 the the DT 1008 1014 T-cell t-cell NN 1015 1023 receptor receptor NN 1024 1025 ( ( ( 1025 1028 TCR TCR NNP 1029 1033 beta beta NN 1033 1034 , , , 1035 1040 gamma gamma NN 1040 1041 , , , 1042 1047 delta delta NN 1047 1048 ) ) ) 1048 1049 . . . 1050 1058 Leukemic leukemic JJ 1059 1065 blasts blast NNS 1066 1068 in in IN 1069 1072 the the DT 1073 1081 majority majority NN 1082 1084 of of IN 1085 1090 cases case NNS 1091 1097 shared share VBD 1098 1104 unique unique JJ 1105 1116 morphologic morphologic JJ 1117 1125 features feature NNS 1126 1127 ( ( ( 1127 1133 deeply deeply RB 1134 1145 invaginated invaginated JJ 1146 1153 nuclear nuclear JJ 1154 1163 membranes membrane NNS 1163 1164 , , , 1165 1170 scant scant JJ 1171 1180 cytoplasm cytoplasm NN 1181 1185 with with IN 1186 1190 fine fine JJ 1191 1202 azurophilic azurophilic JJ 1203 1214 granularity granularity NN 1214 1215 , , , 1216 1219 and and CC 1220 1226 finely finely RB 1227 1235 granular granular JJ 1236 1241 Sudan Sudan NNP 1242 1247 black black JJ 1248 1249 B b NN 1250 1253 and and CC 1254 1269 myeloperoxidase myeloperoxidase NN 1270 1282 cytochemical cytochemical JJ 1283 1293 reactivity reactivity NN 1293 1294 ) ) ) 1295 1299 that that WDT 1300 1304 were be VBD 1305 1315 remarkably remarkably RB 1316 1323 similar similar JJ 1324 1326 to to TO 1327 1332 those those DT 1333 1335 of of IN 1336 1341 acute acute JJ 1342 1355 promyelocytic promyelocytic JJ 1356 1364 leukemia leukemia NN 1365 1366 ( ( ( 1366 1369 APL APL NNP 1369 1370 ) ) ) 1370 1371 ; ; : 1372 1384 particularly particularly RB 1385 1388 the the DT 1389 1402 microgranular microgranular JJ 1403 1410 variant variant NN 1411 1412 ( ( ( 1412 1415 FAB FAB NNP 1416 1423 AML-M3v AML-M3v NNP 1423 1424 ) ) ) 1424 1425 . . . 1426 1433 However however RB 1433 1434 , , , 1435 1438 all all DT 1439 1441 20 20 CD 1442 1447 cases case NNS 1448 1454 lacked lack VBD 1455 1458 the the DT 1459 1467 t(15;17) t(15;17) NN 1468 1471 and and CC 1472 1474 17 17 CD 1475 1480 cases case NNS 1481 1487 tested test VBN 1488 1494 lacked lack VBD 1495 1498 the the DT 1499 1521 promyelocytic/retinoic promyelocytic/retinoic JJ 1522 1526 acid acid NN 1527 1535 receptor receptor NN 1536 1541 alpha alpha NN 1542 1543 ( ( ( 1543 1546 RAR RAR NNP 1547 1552 alpha alpha NN 1552 1553 ) ) ) 1554 1560 fusion fusion NN 1561 1571 transcript transcript NN 1572 1574 in in IN 1575 1581 RT-PCR RT-PCR NNP 1582 1588 assays assay NNS 1588 1589 ; ; : 1590 1592 12 12 CD 1593 1598 cases case NNS 1599 1602 had have VBD 1603 1608 46,XX 46,xx NN 1609 1611 or or CC 1612 1617 46,XY 46,xy NN 1618 1628 karyotypes karyotype NNS 1628 1629 , , , 1630 1637 whereas whereas IN 1638 1639 2 2 CD 1640 1645 cases case NNS 1646 1649 had have VBD 1650 1663 abnormalities abnormality NNS 1664 1666 of of IN 1667 1677 chromosome chromosome NN 1678 1681 17q 17q NN 1681 1682 : : : 1683 1684 1 1 CD 1685 1689 with with IN 1690 1702 del(17)(q25) del(17)(q25) NNP 1703 1706 and and CC 1707 1710 the the DT 1711 1716 other other JJ 1717 1721 with with IN 1722 1739 t(11;17)(q23;q21) t(11;17)(q23;q21) NNP 1740 1743 and and CC 1744 1747 the the DT 1748 1761 promyelocytic promyelocytic JJ 1762 1770 leukemia leukemia NN 1771 1775 zinc zinc NN 1776 1786 finger/RAR finger/RAR NNP 1787 1792 alpha alpha NN 1793 1799 fusion fusion NN 1800 1810 transcript transcript NN 1810 1811 . . . 1812 1815 All all DT 1816 1821 cases case NNS 1822 1828 tested test VBN 1829 1830 ( ( ( 1830 1834 6/20 6/20 CD 1834 1835 ) ) ) 1835 1836 , , , 1837 1846 including include VBG 1847 1850 the the DT 1851 1855 case case NN 1856 1860 with with IN 1861 1869 t(11;17) t(11;17) NNP 1869 1870 , , , 1871 1877 failed fail VBD 1878 1880 to to TO 1881 1894 differentiate differentiate VB 1895 1897 in in FW 1898 1903 vitro vitro FW 1904 1906 in in IN 1907 1915 response response NN 1916 1918 to to TO 1919 1928 all-trans all-trans JJ 1929 1937 retinoic retinoic JJ 1938 1942 acid acid NN 1943 1944 ( ( ( 1944 1948 ATRA ATRA NNP 1948 1949 ) ) ) 1949 1950 , , , 1951 1961 suggesting suggest VBG 1962 1966 that that IN 1967 1972 these these DT 1973 1978 cases case NNS 1979 1982 may may MD 1983 1990 account account VB 1991 1994 for for IN 1995 1999 some some DT 2000 2004 APLs APL NNP 2005 2009 that that WDT 2010 2014 have have VBP 2015 2018 not not RB 2019 2024 shown show VBN 2025 2026 a a DT 2027 2035 clinical clinical JJ 2036 2044 response response NN 2045 2047 to to TO 2048 2052 ATRA ATRA NNP 2052 2053 . . . 2054 2058 Four four CD 2059 2061 of of IN 2062 2063 6 6 CD 2064 2069 cases case NNS 2070 2076 tested test VBN 2077 2083 showed show VBD 2084 2094 functional functional JJ 2095 2097 NK NK NNP 2098 2111 cell-mediated cell-mediated JJ 2112 2124 cytotoxicity cytotoxicity NN 2124 2125 , , , 2126 2136 suggesting suggest VBG 2137 2138 a a DT 2139 2151 relationship relationship NN 2152 2159 between between IN 2160 2165 these these DT 2166 2172 unique unique JJ 2173 2178 CD33+ cd33+ JJ 2178 2179 , , , 2180 2185 CD56+ cd56+ JJ 2185 2186 , , , 2187 2192 CD16- cd16- JJ 2193 2198 acute acute JJ 2199 2208 leukemias leukemia NNS 2209 2212 and and CC 2213 2219 normal normal JJ 2220 2225 CD56+ cd56+ JJ 2225 2226 , , , 2227 2232 CD16- cd16- JJ 2233 2235 NK NK NNP 2236 2245 precursor precursor NN 2246 2251 cells cell NNS 2251 2252 . . . 2253 2258 Using use VBG 2259 2260 a a DT 2261 2272 combination combination NN 2273 2275 of of IN 2276 2283 panning panning NN 2284 2287 and and CC 2288 2302 multiparameter multiparameter NN 2303 2307 flow flow NN 2308 2318 cytometric cytometric JJ 2319 2326 sorting sorting NN 2326 2327 , , , 2328 2330 we we PRP 2331 2341 identified identify VBD 2342 2343 a a DT 2344 2350 normal normal JJ 2351 2356 CD56+ cd56+ JJ 2356 2357 , , , 2358 2363 CD33+ cd33+ JJ 2363 2364 , , , 2365 2370 CD16- cd16- JJ 2371 2382 counterpart counterpart NN 2383 2387 cell cell NN 2388 2390 at at IN 2391 2392 a a DT 2393 2402 frequency frequency NN 2403 2405 of of IN 2406 2407 1 1 CD 2407 2408 % % NN 2409 2411 to to TO 2412 2413 2 2 CD 2413 2414 % % NN 2415 2417 in in IN 2418 2421 the the DT 2422 2432 peripheral peripheral JJ 2433 2438 blood blood NN 2439 2441 of of IN 2442 2449 healthy healthy JJ 2450 2461 individuals individual NNS 2461 2462 . . . 2463 2466 Our our PRP$ 2467 2474 studies study NNS 2475 2482 suggest suggest VBP 2483 2487 that that IN 2488 2492 this this DT 2493 2497 form form NN 2498 2500 of of IN 2501 2506 acute acute JJ 2507 2515 leukemia leukemia NN 2516 2519 may may MD 2520 2525 arise arise VB 2526 2530 from from IN 2531 2545 transformation transformation NN 2546 2548 of of IN 2549 2550 a a DT 2551 2560 precursor precursor NN 2561 2565 cell cell NN 2566 2572 common common JJ 2573 2575 to to TO 2576 2580 both both CC 2581 2584 the the DT 2585 2592 myeloid myeloid JJ 2593 2596 and and CC 2597 2599 NK NK NNP 2600 2604 cell cell NN 2605 2613 lineages lineage NNS 2613 2614 ; ; : 2615 2619 thus thus RB 2620 2622 we we PRP 2623 2630 propose propose VBP 2631 2634 the the DT 2635 2646 designation designation NN 2647 2657 myeloid/NK myeloid/nk NN 2658 2663 acute acute JJ 2664 2672 leukemia leukemia NN 2672 2673 . . . 2674 2685 Recognition Recognition NNP 2686 2688 of of IN 2689 2693 this this DT 2694 2697 new new JJ 2698 2706 leukemic leukemic JJ 2707 2713 entity entity NN 2714 2718 will will MD 2719 2721 be be VB 2722 2731 important important JJ 2732 2734 in in IN 2735 2749 distinguishing distinguish VBG 2750 2755 these these DT 2756 2774 ATRA-nonresponsive atra-nonresponsive JJ 2775 2780 cases case NNS 2781 2785 from from IN 2786 2801 ATRA-responsive atra-responsive JJ 2802 2806 true true JJ 2807 2810 APL apl NN 2810 2811 . . .