{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T15:00:57Z","timestamp":1770822057588,"version":"3.50.1"},"reference-count":40,"publisher":"Proceedings of the National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,6,11]]},"abstract":"<jats:p>\n            Acute promyelocytic leukemia (APL) cells invariably express aberrant fusion proteins involving the retinoic acid receptor \u03b1 (RAR\u03b1). The most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RAR\u03b1 in the balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). Expression of PML\/RAR\u03b1 from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is\n            <jats:italic>FLT3<\/jats:italic>\n            , because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3-ITDs also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML. Here, we test the hypothesis that PML\/RAR\u03b1 can cooperate with FLT3-ITD to induce an APL-like disease in the mouse. Retroviral transduction of FLT3-ITD into bone marrow cells obtained from PML\/RAR\u03b1 transgenic mice results in a short latency APL-like disease with complete penetrance. This disease resembles the APL-like disease that occurs with long latency in the PML\/RAR\u03b1 transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is ATRA responsive. These observations document cooperation between PML\/RAR\u03b1 and FLT3-ITD in development of the murine APL phenotype.\n          <\/jats:p>","DOI":"10.1073\/pnas.122233699","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T14:46:49Z","timestamp":1027694809000},"page":"8283-8288","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":259,"title":["PML\/RAR\u03b1 and FLT3-ITD induce an APL-like disease in a mouse model"],"prefix":"10.1073","volume":"99","author":[{"given":"Louise M.","family":"Kelly","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]},{"given":"Jeffrey L.","family":"Kutok","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]},{"given":"Ifor R.","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]},{"given":"Christina L.","family":"Boulton","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]},{"given":"Sonia M.","family":"Amaral","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]},{"given":"David P.","family":"Curley","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]},{"given":"Timothy J.","family":"Ley","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]},{"given":"D. Gary","family":"Gilliland","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pathology, Brigham and Women's Hospital, and The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; Department of Pathology, Emory University, Atlanta, GA 30322; and Division of Oncology, Washington University Medical School, St. Louis, MO 63110-1092"}]}],"member":"341","published-online":{"date-parts":[[2002,6,11]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.2.376"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.10.5302"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.6.2551"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.20.10901"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)80044-F"},{"key":"e_1_3_3_6_2","first-page":"544","volume":"24","author":"Lavau C","year":"1996","unstructured":"C Lavau, J M Heard, O Danos, A Dejean Exp Hematol 24, 544\u2013551 (1996).","journal-title":"Exp Hematol"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.26.15103"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.24.13306"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.8.2826.bloodjournal8882826"},{"key":"e_1_3_3_10_2","first-page":"929","volume":"8","author":"Warrell R P","year":"1994","unstructured":"R P Warrell, P Maslak, A Eardley, G Heller, W H Miller, S R Frankel Leukemia 8, 929\u2013933 (1994).","journal-title":"Leukemia"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.4.1172"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.4.1192"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.5.1202.bloodjournal8551202"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.3.759"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.6.1752"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2400812"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.8.2434"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.11.3589"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2000.01831.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.12.3907"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203354"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401905"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.1.310"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.18.5321"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.8.1827"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V90.5.1777"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)00067-8"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0215(19991126)83:5<674::AID-IJC18>3.0.CO;2-M"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90322-0"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/1098-2264(2001)9999:9999<::AID-GCC1108>3.0.CO;2-9"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(86)90321-1"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(86)90320-X"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5341.1309"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V93.5.1707"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/13776"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205095"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401130"},{"key":"e_1_3_3_38_2","first-page":"3074","volume":"93","author":"Kiyoi H","year":"1999","unstructured":"H Kiyoi, T Naoe, Y Nakano, S Yokota, S Minami, S Miyawaki, N Asou, K Kuriyama, I Jinnai, C Shimazaki, et al. 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