{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:17:23Z","timestamp":1791231443157,"version":"4.1.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,2,15]]},"abstract":"<jats:p>\n                    P210 Bcr-Abl is an activated tyrosine kinase oncogene encoded by the Philadelphia chromosome associated with human chronic myelogenous leukemia (CML). The disease represents a clonal disorder arising in the pluripotent hematopoietic stem cell. During the chronic phase, patients present with a dramatic expansion of myeloid cells and a mild anemia. Retroviral gene transfer and transgenic expression in rodents have demonstrated the ability of Bcr-Abl to induce various types of leukemia. However, study of human CML or rodent models has not determined the direct and immediate effects of Bcr-Abl on hematopoietic cells from those requiring secondary genetic or epigenetic changes selected during the pathogenic process. We utilized tetracycline-regulated expression of Bcr-Abl from a promoter engineered for robust expression in primitive stem cells through multilineage blood cell development in combination with the\n                    <jats:italic>in vitro<\/jats:italic>\n                    differentiation of embryonal stem cells into hematopoietic elements. Our results demonstrate that Bcr-Abl expression alone is sufficient to increase the number of multipotent and myeloid lineage committed progenitors in a dose-dependent manner while suppressing the development of committed erythroid progenitors. These effects are reversible upon extinguishing Bcr-Abl expression. These findings are consistent with Bcr-Abl being the sole genetic change needed for the establishment of the chronic phase of CML and provide a powerful system for the analysis of any genetic change that alters cell growth and lineage choices of the hematopoietic stem cell.\n                  <\/jats:p>","DOI":"10.1073\/pnas.97.4.1737","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:43:20Z","timestamp":1027680200000},"page":"1737-1742","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":112,"title":["Regulated expression of P210 Bcr-Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate"],"prefix":"10.1073","volume":"97","author":[{"given":"Takumi","family":"Era","sequence":"first","affiliation":[{"name":"Howard Hughes Medical Institute, and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095-1662"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen N.","family":"Witte","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095-1662"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,2,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199909303411407"},{"key":"e_1_3_3_2_2","first-page":"789","volume-title":"The Molecular Basis of Blood Diseases","author":"DeClue J E","year":"1994","unstructured":"J E DeClue, D R Lowy The Molecular Basis of Blood Diseases, eds G Stamatoyannopoulos, A Nienhuis, P Majerus, H Varmus (Saunders, Philadelphia), pp. 789\u2013834 (1994)."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(84)90077-1"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(84)90438-0"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/315550a0"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2400751"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401435"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2237408"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.5.1796.1796"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.8.2171.bloodjournal8582171"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199904293401706"},{"key":"e_1_3_3_12_2","first-page":"20","volume":"25","author":"Bernstein R","year":"1988","unstructured":"R Bernstein Semin Hematol 25, 20\u201334 (1988).","journal-title":"Semin Hematol"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2408149"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.18.6558"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.256.5058.836"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1994.tb06934.x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.23.9312"},{"key":"e_1_3_3_18_2","first-page":"4534","volume":"52","author":"Voncken J W","year":"1992","unstructured":"J W Voncken, S Griffiths, M F Greaves, P K Pattengale, N Heisterkamp, J Groffen Cancer Res 52, 4534\u20134539 (1992).","journal-title":"Cancer Res"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.6.2067"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.10.3780"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.17.6649"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2406902"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.8.3755"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V58.1.158.158"},{"key":"e_1_3_3_25_2","first-page":"1163","volume":"7","author":"Raskind W H","year":"1993","unstructured":"W H Raskind, A M Ferraris, V Najfeld, R J Jacobson, J W Moohr, P J Fialkow Leukemia 7, 1163\u20131167 (1993).","journal-title":"Leukemia"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V86.8.3118.3118"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8066449"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.12.5547"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.13.2048"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/25.14.2723"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(91)90434-D"},{"key":"e_1_3_3_32_2","first-page":"31","volume":"203","author":"Hellen C U","year":"1995","unstructured":"C U Hellen, E Wimmer Curr Top Immunol 203, 31\u201363 (1995).","journal-title":"Curr Top Immunol"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8303295"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.14.3443"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.11.4108"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.57.3.1182-1186.1986"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90111-3"},{"key":"e_1_3_3_38_2","unstructured":"Era T. Takagi T. Takahashi T. Bories J.-C. & Nakano T. (2000) Blood in press."},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5262.722"},{"key":"e_1_3_3_40_2","volume-title":"The Molecular Pathogenesis of the Philadelphia-Positive Leukemias: Implications for Diagnosis and Therapy","author":"Van Etten R A","year":"1993","unstructured":"R A Van Etten The Molecular Pathogenesis of the Philadelphia-Positive Leukemias: Implications for Diagnosis and Therapy (Klumer Academic, Norwood, 1993)."},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199907153410306"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.4.1207"},{"key":"e_1_3_3_43_2","first-page":"1517","volume":"94","author":"Silver R T","year":"1999","unstructured":"R T Silver, S H Woolf, R Hehlmann, F R Appelbaum, J Anderson, C Bennett, J M Goldman, F Guilhot, H M Kantarjian, A E Lichtin, et al. Blood 94, 1517\u20131536 (1999).","journal-title":"Blood"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.7.2200.419a33_2200_2207"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.22.12804"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201664"},{"key":"e_1_3_3_47_2","first-page":"1683","volume":"7","author":"Clarkson B","year":"1993","unstructured":"B Clarkson, A Strife Leukemia 7, 1683\u20131721 (1993).","journal-title":"Leukemia"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1980.tb05929.x"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1996.d01-1738.x"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V82.12.3524.3524"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8652(199907)61:3<178::AID-AJH4>3.0.CO;2-8"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V81.11.2898.2898"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.97.4.1737","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T17:11:36Z","timestamp":1649869896000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.97.4.1737"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,2,15]]},"references-count":52,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2000,2,15]]}},"alternative-id":["10.1073\/pnas.97.4.1737"],"URL":"https:\/\/doi.org\/10.1073\/pnas.97.4.1737","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,2,15]]},"assertion":[{"value":"1999-12-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-02-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}