{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:56:22Z","timestamp":1789718182161,"version":"4.0.1"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1996,11,12]]},"abstract":"<jats:p>\n                    Blastic transformation of chronic myelogenous leukemia (CML) is\n characterized by the presence of nonrandom, secondary genetic\n abnormalities in the majority of Philadelphia\n                    <jats:sup>1<\/jats:sup>\n                    clones, and\n loss of p53 tumor suppressor gene function is a consistent finding in\n 25\u201330% of CML blast crisis patients. To test whether the functional\n loss of p53 plays a direct role in the transition of chronic phase to\n blast crisis, bone marrow cells from p53\n                    <jats:sup>+\/+<\/jats:sup>\n                    or\n p53\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice were infected with a retrovirus carrying\n either the wild-type BCR\/ABL or the inactive kinase-deficient\n mutant, and were assessed for colony-forming ability. Infection of\n p53\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    marrow cells with wild-type BCR\/ABL, but not\n with the kinase-deficient mutant, enhanced formation of hematopoietic\n colonies and induced growth factor independence at high frequency, as\n compared with p53\n                    <jats:sup>+\/+<\/jats:sup>\n                    marrow cells. These effects were\n suppressed when p53\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    marrow cells were coinfected with\n BCR\/ABL and wild-type p53. p53-deficient BCR\/ABL-infected marrow\n cells had a proliferative advantage, as reflected by an increase in the\n fraction of S+G\n                    <jats:sub>2<\/jats:sub>\n                    phase cells and a decrease in the number\n of apoptotic cells. Immunophenotyping and morphological\n analysis revealed that BCR\/ABL-positive p53\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells\n were much less differentiated than their BCR\/ABL-positive\n p53\n                    <jats:sup>+\/+<\/jats:sup>\n                    counterparts. Injection of immunodeficient mice with\n BCR\/ABL-positive p53\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells produced a\n transplantable, highly aggressive, poorly differentiated acute\n myelogenous leukemia. In marked contrast, the disease process in mice\n injected with BCR\/ABL-positive p53\n                    <jats:sup>+\/+<\/jats:sup>\n                    marrow cells was\n characterized by cell infiltrates with a more differentiated phenotype\n and was significantly retarded, as indicated by a much longer survival\n of leukemic mice. Together, these findings directly demonstrate that\n loss of p53 function plays an important role in blast transformation in\n CML.\n                  <\/jats:p>","DOI":"10.1073\/pnas.93.23.13137","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:43:20Z","timestamp":1027680200000},"page":"13137-13142","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":75,"title":["Blastic transformation of p53-deficient bone marrow cells by p210\n                    <sup>bcr\/abl<\/sup>\n                    tyrosine\u2009kinase"],"prefix":"10.1073","volume":"93","author":[{"given":"Tomasz","family":"Skorski","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer\r Institute, Thomas Jefferson University, Philadelphia, PA 19107; and\r Department of Pathology and Laboratory Medicine, University of\r Pennsylvania, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Nieborowska-Skorska","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer\r Institute, Thomas Jefferson University, Philadelphia, PA 19107; and\r Department of Pathology and Laboratory Medicine, University of\r Pennsylvania, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Wlodarski","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer\r Institute, Thomas Jefferson University, Philadelphia, PA 19107; and\r Department of Pathology and Laboratory Medicine, University of\r Pennsylvania, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilo","family":"Perrotti","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer\r Institute, Thomas Jefferson University, Philadelphia, PA 19107; and\r Department of Pathology and Laboratory Medicine, University of\r Pennsylvania, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer\r Institute, Thomas Jefferson University, Philadelphia, PA 19107; and\r Department of Pathology and Laboratory Medicine, University of\r Pennsylvania, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz\u2009A.","family":"Wasik","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer\r Institute, Thomas Jefferson University, Philadelphia, PA 19107; and\r Department of Pathology and Laboratory Medicine, University of\r Pennsylvania, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Calabretta","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer\r Institute, Thomas Jefferson University, Philadelphia, PA 19107; and\r Department of Pathology and Laboratory Medicine, University of\r Pennsylvania, Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1996,11,12]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V82.3.691.691"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/300765a0"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(84)90438-0"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2406902"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.17.6649"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)60423-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/319783a0"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.8.2391.2391"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/356215a0"},{"key":"e_1_3_2_10_2","first-page":"1079","volume":"247","author":"Pendergast A 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