{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T20:37:00Z","timestamp":1793479020009,"version":"4.5.0"},"reference-count":17,"publisher":"National Academy of Sciences","issue":"33","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,8,13]]},"abstract":"<jats:p>\n                    Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding. The mechanism by which AML mediates this complication is unknown but one widely accepted explanation is that AML depletes the BM of hematopoietic stem cells (HSCs) through displacement. We sought to investigate how AML affects hematopoiesis by quantifying residual normal hematopoietic subpopulations in the BM of immunodeficient mice transplanted with human AML cells with a range of genetic lesions. The numbers of normal mouse HSCs were preserved whereas normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs, findings consistent with a differentiation block at the HSC\u2013progenitor transition, rather than displacement. Once removed from the leukemic environment, residual normal hematopoietic cells differentiated normally and outcompeted steady-state hematopoietic cells, indicating that this effect is reversible. We confirmed the clinical significance of this by ex vivo analysis of normal hematopoietic subpopulations from BM of 16 patients with AML. This analysis demonstrated that the numbers of normal CD34\n                    <jats:sup>+<\/jats:sup>\n                    CD38\n                    <jats:sup>\u2212<\/jats:sup>\n                    stem-progenitor cells were similar in the BM of AML patients and controls, whereas normal CD34\n                    <jats:sup>+<\/jats:sup>\n                    CD38\n                    <jats:sup>+<\/jats:sup>\n                    progenitors were reduced. Residual normal CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells from patients with AML were enriched in long-term culture, initiating cells and repopulating cells compared with controls. In conclusion the data do not support the idea that BM failure in AML is due to HSC depletion. Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC\u2013progenitor transition.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1301891110","type":"journal-article","created":{"date-parts":[[2013,7,31]],"date-time":"2013-07-31T03:25:22Z","timestamp":1375241122000},"page":"13576-13581","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":142,"title":["Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation"],"prefix":"10.1073","volume":"110","author":[{"given":"Farideh","family":"Miraki-Moud","sequence":"first","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Anjos-Afonso","sequence":"additional","affiliation":[{"name":"Haematopoietic Stem Cell Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine A.","family":"Hodby","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Griessinger","sequence":"additional","affiliation":[{"name":"Haematopoietic Stem Cell Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guglielmo","family":"Rosignoli","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core Facility, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Lillington","sequence":"additional","affiliation":[{"name":"Cytogenetics Department, Royal London Hospital, London E1 2ES, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff K.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Cavenagh","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Oakervee","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Gribben","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Bonnet","sequence":"additional","affiliation":[{"name":"Haematopoietic Stem Cell Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Taussig","sequence":"additional","affiliation":[{"name":"Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,7,30]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.10.048"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2726"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2007.0017"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.21723"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1350"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.121"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.05.026"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-02-206565"},{"key":"e_1_3_3_9_2","first-page":"983","article-title":"Assessment of the normal or leukemic nature of CD34+ cells in acute myeloid leukemia with low percentages of CD34 cells","volume":"88","author":"van der Pol MA","year":"2003","unstructured":"MA van der Pol, et al., Assessment of the normal or leukemic nature of CD34+ cells in acute myeloid leukemia with low percentages of CD34 cells. Haematologica 88, 983\u2013993 (2003).","journal-title":"Haematologica"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.172384399"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1201219"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-12-192922"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.5.1302"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(94)91579-2"},{"key":"e_1_3_3_15_2","doi-asserted-by":"crossref","unstructured":"Jan M et al. (2012) Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. 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