{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:16:11Z","timestamp":1791353771910,"version":"4.3.1"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2010,12,3]],"date-time":"2010-12-03T00:00:00Z","timestamp":1291334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2011,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although tyrosine kinase inhibitors have redefined the care of chronic myeloid leukemia (CML), these agents have not proved curative, likely due to resistance of the leukemia stem cells (LSC). While a number of potential therapeutic targets have emerged in CML, their expression in the LSC remains largely unknown. We therefore isolated subsets of CD34<jats:sup>+<\/jats:sup> stem\/progenitor cells from normal donors and from patients with chronic phase or blast crisis CML. These cell subsets were then characterized based on ability to engraft immunodeficient mice and expression of candidate therapeutic targets. The CD34<jats:sup>+<\/jats:sup>CD38<jats:sup>\u2212<\/jats:sup> CML cell population with high aldehyde dehydrogenase (ALDH) activity was the most enriched for immunodeficient mouse engrafting capacity. The putative targets: <jats:italic>PROTEINASE 3<\/jats:italic>, <jats:italic>SURVIVIN<\/jats:italic>, and <jats:italic>hTERT<\/jats:italic> were expressed only at relatively low levels by the CD34<jats:sup>+<\/jats:sup>CD38<jats:sup>\u2212<\/jats:sup>ALDH<jats:sup>high<\/jats:sup> CML cells, similar to the normal CD34<jats:sup>+<\/jats:sup>CD38<jats:sup>\u2212<\/jats:sup>ALDH<jats:sup>high<\/jats:sup> cells and less than in the total CML CD34<jats:sup>+<\/jats:sup> cells. In fact, the highest expression of these antigens was in normal, unfractionated CD34<jats:sup>+<\/jats:sup> cells. In contrast, <jats:italic>PRAME<\/jats:italic> and <jats:italic>WT1<\/jats:italic> were more highly expressed by all CML CD34<jats:sup>+<\/jats:sup> subsets than their normal counterparts. Thus, ALDH activity appears to enrich for CML stem cells, which display an expression profile that is distinct from normal stem\/progenitor cells and even the CML progenitors. Indeed, expression of a putative target by the total CD34<jats:sup>+<\/jats:sup> population in CML does not guarantee expression by the LSC. These expression patterns suggest that <jats:italic>PROTEINASE 3, SURVIVIN,<\/jats:italic> and <jats:italic>hTERT<\/jats:italic> are not optimal therapeutic targets in CML stem cells; whereas <jats:italic>PRAME<\/jats:italic> and <jats:italic>WT1<\/jats:italic> seem promising. Am. J. Hematol., 2011. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajh.21915","type":"journal-article","created":{"date-parts":[[2010,10,27]],"date-time":"2010-10-27T18:20:15Z","timestamp":1288203615000},"page":"31-37","source":"Crossref","is-referenced-by-count":79,"title":["Characterization of chronic myeloid leukemia stem cells"],"prefix":"10.1002","volume":"86","author":[{"given":"Jonathan M.","family":"Gerber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Kowalski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Douglas","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance A.","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milada S.","family":"Vala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael I.","family":"Collector","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandy","family":"Perkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Zahurak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Matsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Gocke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saul J.","family":"Sharkis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyam I.","family":"Levitsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,12,3]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1056\/NEJM200104053441401","article-title":"Efficacy and safety of a specific inhibitor of the BCR\u2010ABL tyrosine kinase in chronic myeloid leukemia","volume":"344","author":"Druker BJ","journal-title":"N Engl J Med"},{"key":"e_1_2_6_3_2","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1182\/blood-2003-11-3800","article-title":"High\u2010dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome\u2010positive chronic phase chronic myeloid leukemia","volume":"103","author":"Kantarjian H","journal-title":"Blood"},{"key":"e_1_2_6_4_2","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1182\/blood-2004-04-1335","article-title":"Discontinuation of imatinib therapy after achieving a molecular response","volume":"104","author":"Cortes J","journal-title":"Blood"},{"key":"e_1_2_6_5_2","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1182\/blood-2006-03-011239","article-title":"Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years","volume":"109","author":"Rousselot P","journal-title":"Blood"},{"key":"e_1_2_6_6_2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1182\/blood.V99.1.319","article-title":"Primitive, quiescent, Philadelphia\u2010positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro","volume":"99","author":"Graham SM","journal-title":"Blood"},{"key":"e_1_2_6_7_2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/j.1365-2141.2005.05606.x","article-title":"Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors","volume":"130","author":"Angstreich GR","journal-title":"Br J Haematol"},{"key":"e_1_2_6_8_2","doi-asserted-by":"crossref","first-page":"4532","DOI":"10.1182\/blood-2005-07-2947","article-title":"Dasatinib (BMS\u2010354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction","volume":"107","author":"Copland M","journal-title":"Blood"},{"key":"e_1_2_6_9_2","doi-asserted-by":"crossref","first-page":"4701","DOI":"10.1182\/blood-2002-09-2780","article-title":"Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment","volume":"101","author":"Bhatia R","journal-title":"Blood"},{"issue":"2","key":"e_1_2_6_10_2","first-page":"S31","article-title":"Advanced CML: Therapeutic options for patients in accelerated and blast phases","volume":"6","author":"Shah NP","journal-title":"J Natl Compr Canc Netw"},{"key":"e_1_2_6_11_2","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nrc2368","article-title":"Getting to the stem of chronic myeloid leukaemia","volume":"8","author":"Savona M","journal-title":"Nat Rev Cancer"},{"key":"e_1_2_6_12_2","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/hon.813","article-title":"Therapeutic targets in chronic myeloid leukaemia","volume":"25","author":"Heaney NB","journal-title":"Hematol Oncol"},{"key":"e_1_2_6_13_2","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1038\/leu.2008.161","article-title":"Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia\u2010associated antigens: Implications for the graft\u2010versus\u2010leukemia effect and peptide vaccine\u2010based immunotherapy","volume":"22","author":"Yong AS","journal-title":"Leukemia"},{"key":"e_1_2_6_14_2","first-page":"1653","article-title":"Cancer vaccines for patients with acute myeloid leukemia\u2014Definition of leukemia\u2010associated antigens and current clinical protocols targeting these antigens","volume":"91","author":"Greiner J","journal-title":"Haematologica"},{"key":"e_1_2_6_15_2","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1038\/sj.leu.2404924","article-title":"Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR\/ABL1 mediates resistance to imatinib in human leukaemia cells","volume":"21","author":"Svensson E","journal-title":"Leukemia"},{"key":"e_1_2_6_16_2","first-page":"589","article-title":"Expression of the antiapoptotic gene survivin in chronic myeloid leukemia","volume":"23","author":"Badran A","journal-title":"Anticancer Res"},{"key":"e_1_2_6_17_2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/j.1600-0609.2008.01053.x","article-title":"Leukemia\u2010associated antigens as target structures for a specific immunotherapy in chronic myeloid leukemia","volume":"80","author":"Greiner J","journal-title":"Eur J Haematol"},{"key":"e_1_2_6_18_2","article-title":"Telomerase and its potential for therapeutic intervention","author":"Phatak P","journal-title":"Br J Pharmacol"},{"key":"e_1_2_6_19_2","doi-asserted-by":"crossref","first-page":"8014","DOI":"10.1158\/0008-5472.CAN-07-1343","article-title":"YM155, a novel small\u2010molecule survivin suppressant, induces regression of established human hormone\u2010refractory prostate tumor xenografts","volume":"67","author":"Nakahara T","journal-title":"Cancer Res"},{"key":"e_1_2_6_20_2","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1182\/blood.V81.11.2898.2898","article-title":"BCR\u2010ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia","volume":"81","author":"Bedi A","journal-title":"Blood"},{"key":"e_1_2_6_21_2","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.tcb.2005.07.004","article-title":"Cancer stem cells: Lessons from leukemia","volume":"15","author":"Wang JC","journal-title":"Trends Cell Biol"},{"key":"e_1_2_6_22_2","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1038\/sj.leu.2404401","article-title":"Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells","volume":"20","author":"Gal H","journal-title":"Leukemia"},{"key":"e_1_2_6_23_2","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1365-2141.2005.05596.x","article-title":"Normal and leukaemic stem cells","volume":"130","author":"Bonnet D","journal-title":"Br J Haematol"},{"key":"e_1_2_6_24_2","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.3324\/haematol.11366","article-title":"Improved purification of hematopoietic stem cells based on their elevated aldehyde dehydrogenase activity","volume":"92","author":"Christ O","journal-title":"Haematologica"},{"key":"e_1_2_6_25_2","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1002\/stem.186","article-title":"Dual SP\/ALDH functionalities refine the human hematopoietic Lin(\u2010)CD34(+)CD38(\u2010) stem\/progenitor cell compartment","volume":"27","author":"Pierre\u2010Louis O","journal-title":"Stem Cells"},{"key":"e_1_2_6_26_2","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1016\/S0140-6736(05)66515-4","article-title":"Aplastic anaemia","volume":"365","author":"Brodsky RA","journal-title":"Lancet"},{"key":"e_1_2_6_27_2","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1158\/0008-5472.CAN-07-3096","article-title":"Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance","volume":"68","author":"Matsui W","journal-title":"Cancer Res"},{"key":"e_1_2_6_28_2","doi-asserted-by":"crossref","first-page":"5920","DOI":"10.1182\/blood-2008-11-189688","article-title":"Circulating clonotypic B cells in classic Hodgkin lymphoma","volume":"113","author":"Jones RJ","journal-title":"Blood"},{"key":"e_1_2_6_29_2","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1182\/blood.V85.10.2742.bloodjournal85102742","article-title":"Assessment of aldehyde dehydrogenase in viable cells","volume":"85","author":"Jones RJ","journal-title":"Blood"},{"key":"e_1_2_6_30_2","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.leukres.2006.02.031","article-title":"PRAME is a membrane and cytoplasmic protein aberrantly expressed in chronic lymphocytic leukemia and mantle cell lymphoma","volume":"30","author":"Proto\u2010Siqueira R","journal-title":"Leuk Res"},{"key":"e_1_2_6_31_2","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1182\/blood.V87.4.1539.bloodjournal8741539","article-title":"Normal and leukemic SCID\u2010repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis","volume":"87","author":"Sirard C","journal-title":"Blood"},{"key":"e_1_2_6_32_2","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/367645a0","article-title":"A cell initiating human acute myeloid leukaemia after transplantation into SCID mice","volume":"367","author":"Lapidot T","journal-title":"Nature"},{"key":"e_1_2_6_33_2","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1111\/j.1365-2141.1995.tb03297.x","article-title":"Immunocytochemical and flow cytometric detection of proteinase 3 (myeloblastin) in normal and leukaemic myeloid cells","volume":"89","author":"Dengler R","journal-title":"Br J Haematol"},{"key":"e_1_2_6_34_2","first-page":"59","article-title":"Expression of the anti\u2010apoptotic gene survivin in myelodysplastic syndrome","volume":"22","author":"Badran A","journal-title":"Int J Oncol"},{"key":"e_1_2_6_35_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-1119(01)00440-1","article-title":"Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT)","volume":"269","author":"Poole JC","journal-title":"Gene"},{"key":"e_1_2_6_36_2","first-page":"326","article-title":"WT1 and BCR\u2010ABL specific small interfering RNA have additive effects in the induction of apoptosis in leukemic cells","volume":"90","author":"Elmaagacli AH","journal-title":"Haematologica"},{"key":"e_1_2_6_37_2","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/sj.bmt.1704620","article-title":"Monitoring of minimal residual disease using WT1 assay for patients with chronic myeloid leukemia who undergo allogeneic stem cell transplantation","volume":"34","author":"Tamaki H","journal-title":"Bone Marrow Transplant"},{"key":"e_1_2_6_38_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1159\/000077562","article-title":"WT1 as a universal marker for minimal residual disease detection and quantification in myeloid leukemias and in myelodysplastic syndrome","volume":"112","author":"Cilloni D","journal-title":"Acta Haematol"},{"key":"e_1_2_6_39_2","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.coi.2006.07.005","article-title":"Immunotherapeutic peptide vaccination with leukemia\u2010associated antigens","volume":"18","author":"Rusakiewicz S","journal-title":"Curr Opin Immunol"},{"key":"e_1_2_6_40_2","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1038\/sj.leu.2404878","article-title":"Effective treatment of leukemic cell lines with wt1 siRNA","volume":"21","author":"Glienke W","journal-title":"Leukemia"},{"key":"e_1_2_6_41_2","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1073\/pnas.0510423103","article-title":"Gene expression changes associated with progression and response in chronic myeloid leukemia","volume":"103","author":"Radich JP","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_2_6_42_2","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.cell.2005.07.003","article-title":"The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling","volume":"122","author":"Epping MT","journal-title":"Cell"},{"key":"e_1_2_6_43_2","doi-asserted-by":"crossref","first-page":"3299","DOI":"10.1182\/blood-2008-07-170282","article-title":"The preferentially expressed antigen in melanoma (PRAME) inhibits myeloid differentiation in normal hematopoietic and leukemic progenitor cells","volume":"114","author":"Oehler VG","journal-title":"Blood"},{"key":"e_1_2_6_44_2","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1089\/10430349950017347","article-title":"A universal granulocyte\u2010macrophage colony\u2010stimulating factor\u2010producing bystander cell line for use in the formulation of autologous tumor cell\u2010based vaccines","volume":"10","author":"Borrello I","journal-title":"Hum Gene Ther"},{"key":"e_1_2_6_45_2","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1158\/1078-0432.CCR-09-2046","article-title":"K562\/GM\u2010CSF immunotherapy reduces tumor burden in chronic myeloid leukemia patients with residual disease on imatinib mesylate","volume":"16","author":"Smith BD","journal-title":"Clin Cancer Res"},{"key":"e_1_2_6_46_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.blre.2009.11.002","article-title":"Optimising chronic myeloid leukaemia therapy in the face of resistance to tyrosine kinase inhibitors\u2014A synthesis of clinical and laboratory data","volume":"24","author":"Irvine DA","journal-title":"Blood Rev"}],"container-title":["American Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajh.21915","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.21915","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T14:18:45Z","timestamp":1697465925000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajh.21915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,12,3]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,1]]}},"alternative-id":["10.1002\/ajh.21915"],"URL":"https:\/\/doi.org\/10.1002\/ajh.21915","archive":["Portico"],"relation":{},"ISSN":["0361-8609","1096-8652"],"issn-type":[{"value":"0361-8609","type":"print"},{"value":"1096-8652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,12,3]]}}}