{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T09:41:47Z","timestamp":1791106907524,"version":"4.1.0"},"reference-count":78,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,1,7]],"date-time":"2013-01-07T00:00:00Z","timestamp":1357516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2013,3]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Infants with <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010rearranged (<jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R) acute lymphoblastic leukaemia (<jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>) have a dismal prognosis. While most patients achieve remission, approximately half of patients recur with a short latency to relapse. This suggests that chemotherapy\u2010resistant leukaemia stem cells (<jats:styled-content style=\"fixed-case\">LSC<\/jats:styled-content>s) survive and can recapitulate the leukaemia. We hypothesized that interactions between <jats:styled-content style=\"fixed-case\">LSC<\/jats:styled-content>s and the bone marrow microenvironment mediate survival and chemotherapy resistance in <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>. Using primary samples of infant <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>, we studied the influence of bone marrow stroma on apoptosis, proliferation, and cytotoxicity induced by the <jats:styled-content style=\"fixed-case\">FLT<\/jats:styled-content>3 inhibitor lestaurtinib. <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content> were differentially protected by stroma from spontaneous apoptosis compared to non\u2010<jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>. Co\u2010culture of bulk <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content> in direct contact with stroma or with stroma\u2010produced soluble factors promoted proliferation and cell cycle entry. Stroma also protected bulk <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content> cells and <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL LSC<\/jats:styled-content>s from lestaurtinib\u2010mediated cytotoxicity. Previous studies have demonstrated that <jats:styled-content style=\"fixed-case\">CXCR<\/jats:styled-content>4 mediates bone marrow microenvironment signalling. Using a xenograft model of <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>, we demonstrated that <jats:styled-content style=\"fixed-case\">CXCR<\/jats:styled-content>4 inhibition with <jats:styled-content style=\"fixed-case\">AMD<\/jats:styled-content>3100 (plerixafor) led to markedly enhanced efficacy of lestaurtinib. Therefore, the bone marrow microenvironment is a mediator of chemotherapy resistance in <jats:italic><jats:styled-content style=\"fixed-case\">MLL<\/jats:styled-content><\/jats:italic>\u2010R <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content> and targeting leukaemia\u2010stroma interactions with <jats:styled-content style=\"fixed-case\">CXCR<\/jats:styled-content>4 inhibitors may prove useful in this high\u2010risk subtype of paediatric <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/bjh.12205","type":"journal-article","created":{"date-parts":[[2013,1,7]],"date-time":"2013-01-07T13:33:04Z","timestamp":1357565584000},"page":"785-797","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["<i><scp>MLL<\/scp><\/i>\u2010rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with <scp>CXCR<\/scp>4 antagonism"],"prefix":"10.1111","volume":"160","author":[{"given":"Edward Allan R.","family":"Sison","sequence":"first","affiliation":[{"name":"Oncology and Pediatrics The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel E.","family":"Rau","sequence":"additional","affiliation":[{"name":"Pediatric Hematology\/Oncology Texas Children's Cancer and Hematology Centers Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Oncology and Pediatrics The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Oncology and Pediatrics The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald","family":"Small","sequence":"additional","affiliation":[{"name":"Oncology and Pediatrics The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Brown","sequence":"additional","affiliation":[{"name":"Oncology and Pediatrics The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,1,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.07.004"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng765"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.175"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2011.1.354"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.14.4519"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.3.1101"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.5.753"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401729"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-06-2498"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2404277"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041385"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.8.2655"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2003.04466.x"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.11.002"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02040"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2008.08.011"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164390"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2001.03164.x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.07.131"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.20.7209"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-174946"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.6.3903"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.8018"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1350"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2009.12.003"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-07-0042"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402998"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2404684"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-218560"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22510"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.26113"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402608"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.9.6.11011"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2253"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2005.08.003"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1537-2995.2005.04222.x"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.16.9448"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm909"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09262"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1041"},{"key":"e_1_2_7_42_1","doi-asserted-by":"crossref","first-page":"4523","DOI":"10.1182\/blood.V91.12.4523","article-title":"The chemokine receptor CXCR\u20104 is expressed on CD34\u00a0+\u00a0 hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell\u2010derived factor\u20101","volume":"91","author":"Mohle R.","year":"1998","journal-title":"Blood"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.5.1926"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.6.2305"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/382635a0"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-06-162123"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1103154108"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.76"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5403.845"},{"key":"e_1_2_7_50_1","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1182\/blood.V95.11.3289","article-title":"The chemokine SDF\u20101 activates the integrins LFA\u20101, VLA\u20104, and VLA\u20105 on immature human CD34\u00a0+\u00a0cells: role in transendothelial\/stromal migration and engraftment of NOD\/SCID mice","volume":"95","author":"Peled A.","year":"2000","journal-title":"Blood"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.182.1.604"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11899-009-0023-4"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61126-X"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201102131"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.30.7405"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403253"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-02-0566"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-01-0338"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.261"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-243634"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2002.03835_6.x"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-01-024729"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.21.2514"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-472X(01)00741-X"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1996.14.1.18"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.388"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-024844"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-02-205963"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3166"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-3693"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.238"},{"key":"e_1_2_7_72_1","first-page":"4882","article-title":"Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements","volume":"63","author":"Tsutsumi S.","year":"2003","journal-title":"Cancer Research"},{"key":"e_1_2_7_73_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1182\/blood.V118.21.82.82","article-title":"Safety and tolerability of plerixafor in combination with cytarabine and daunorubicin in patients with newly diagnosed acute myeloid leukemia\u2010 preliminary results from a phase I study","volume":"118","author":"Uy G.L.","year":"2011","journal-title":"Blood"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-383406"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.17"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00032-6"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28568"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-158311"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10334"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbjh.12205","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbjh.12205","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.12205","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T00:50:43Z","timestamp":1700614243000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.12205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,7]]},"references-count":78,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2013,3]]}},"alternative-id":["10.1111\/bjh.12205"],"URL":"https:\/\/doi.org\/10.1111\/bjh.12205","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,1,7]]},"assertion":[{"value":"2012-10-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-11-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-01-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}