{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:30:28Z","timestamp":1793089828153,"version":"4.5.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000294","name":"Medical Research Scotland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000294","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Commun Signal"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite improved patient outcome using tyrosine kinase inhibitors (TKIs), chronic myeloid leukaemia (CML) patients require life-long treatment due to leukaemic stem cell (LSC) persistence. LSCs reside in the bone marrow (BM) niche, which they modify to their advantage. The BM provides oncogene-independent signals to aid LSC cell survival and quiescence. The bone-morphogenetic pathway (BMP) is one pathway identified to be highly deregulated in CML, with high levels of BMP ligands detected in the BM, accompanied by CML stem and progenitor cells overexpressing BMP type 1 receptors- activin-like kinases (ALKs), especially in TKI resistant patients. Saracatinib (SC), a SRC\/ABL1 dual inhibitor, inhibits the growth of CML cells resistant to the TKI imatinib (IM). Recent studies indicate that SC is also a potent ALK inhibitor and BMP antagonist. Here we investigate the efficacy of SC in overcoming CML BCR::ABL1 dependent and independent signals mediated by the BM niche both in 2D and 3D culture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CML cells (K562 cell line and CML CD34\n                      <jats:sup>+<\/jats:sup>\n                      primary cells) were treated with single or combination treatments of: IM, SC and the BMP receptors inhibitor dorsomorphin (DOR), with or without BMP4 stimulation in 2D (suspension) and 3D co-culture on HS5 stroma cell line and mesenchymal stem cells in AggreWell and microfluidic devices. Flow cytometry was performed to investigate apoptosis, cell cycle progression and proliferation, alongside colony assays following treatment. Proteins changes were validated by immunoblotting and transcriptional changes by Fluidigm multiplex qPCR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      By targeting the BMP pathway, using specific inhibitors against ALKs in combination with SRC and ABL TKIs, we show an increase in apoptosis, altered cell cycle regulation, fewer cell divisions, and reduced numbers of CD34\n                      <jats:sup>+<\/jats:sup>\n                      cells. Impairment of long-term proliferation and differentiation potential after combinatorial treatment also occurred.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>BMP signalling pathway is important for CML cell survival. Targeting SRC, ABL and ALK kinases is more effective than ABL inhibition alone, the combination efficacy importantly being demonstrated in both 2D and 3D cell cultures highlighting the need for combinatorial therapies in contrast to standard of care single agents. Our study provides justification to target multiple kinases in CML to combat LSC persistence.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-023-01363-2","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T04:03:15Z","timestamp":1701230595000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach"],"prefix":"10.1186","volume":"21","author":[{"given":"Caroline","family":"Busch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Mulholland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Zagnoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Dalby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Berry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Wheadon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"1363_CR1","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/s41375-020-0776-2","volume":"34","author":"A Hochhaus","year":"2020","unstructured":"Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. Chronic myelogenous leukemia European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966\u201384. https:\/\/doi.org\/10.1038\/s41375-020-0776-2.","journal-title":"Leukemia"},{"key":"1363_CR2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.leukres.2013.09.011","volume":"38","author":"S Soverini","year":"2014","unstructured":"Soverini S, Branford S, Nicolini FE, Talpaz M, Deininger MW, Martinelli G, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38:10. https:\/\/doi.org\/10.1016\/j.leukres.2013.09.011.","journal-title":"Leuk Res."},{"key":"1363_CR3","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1182\/blood-2016-04-708560","volume":"129","author":"T Kim","year":"2016","unstructured":"Kim T, Tyndel MS, Joon Kim H, Ahn JS, Hyun Choi S, Jeong Park H, et al. Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy Running Title: Dynamic patterns of somatic mutations in CML. Blood. 2016;129:38\u201347. https:\/\/doi.org\/10.1182\/blood-2016-04-708560.","journal-title":"Blood"},{"key":"1363_CR4","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1038\/sj.leu.2404318","volume":"20","author":"E Jabbour","year":"2006","unstructured":"Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O\u2019Brien S, et al. Frequency and clinical significance of BCR::ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20:1767\u201373. https:\/\/doi.org\/10.1038\/sj.leu.2404318.","journal-title":"Leukemia"},{"key":"1363_CR5","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1056\/NEJMoa1306494","volume":"369","author":"JE Cortes","year":"2013","unstructured":"Cortes JE, Kim DW, Pinilla-Ibarz J, Le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783\u201396. https:\/\/doi.org\/10.1056\/NEJMoa1306494.","journal-title":"N Engl J Med"},{"key":"1363_CR6","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1177\/2040620715607416","volume":"6","author":"S Giri","year":"2015","unstructured":"Giri S, Pathak R, Martin MG, Bhatt VR. Characteristics and survival of BCR\/ABL negative chronic myeloid leukemia: a retrospective analysis of the surveillance, epidemiology and end results database. Ther Adv Hematol. 2015;6:308\u201312. https:\/\/doi.org\/10.1177\/2040620715607416.","journal-title":"Ther Adv Hematol"},{"key":"1363_CR7","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1172\/JCI35721","volume":"121","author":"AS Corbin","year":"2011","unstructured":"Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR::ABL activity. J Clin Invest. 2011;121:396\u2013409. https:\/\/doi.org\/10.1172\/JCI35721.","journal-title":"J Clin Invest"},{"key":"1363_CR8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.exphem.2016.11.005","volume":"47","author":"CJ Clarke","year":"2017","unstructured":"Clarke CJ, Holyoake TL. Preclinical approaches in chronic myeloid leukemia: from cells to systems. Exp Hematol. 2017;47:13\u201323. https:\/\/doi.org\/10.1016\/j.exphem.2016.11.005.","journal-title":"Exp Hematol"},{"key":"1363_CR9","doi-asserted-by":"publisher","first-page":"4820","DOI":"10.3390\/cancers13194820","volume":"13","author":"R Alves","year":"2021","unstructured":"Alves R, Gon\u00e7alves AC, Rutella S, Almeida AM, De Las RJ, Trougakos IP, et al. Resistance to tyrosine kinase inhibitors in chronic myeloid leukemia\u2014from molecular mechanisms to clinical relevance. Cancers. 2021;13:4820. https:\/\/doi.org\/10.3390\/cancers13194820.","journal-title":"Cancers"},{"key":"1363_CR10","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1002\/path.2793","volume":"223","author":"MR Alison","year":"2011","unstructured":"Alison MR, Lim SM, Nicholson LJ. Cancer stem cells: problems for therapy? J Pathol. 2011;223:148\u201362. https:\/\/doi.org\/10.1002\/path.2793.","journal-title":"J Pathol"},{"key":"1363_CR11","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.clml.2011.10.003","volume":"12","author":"TA Baghdadi","year":"2012","unstructured":"Baghdadi TA, Abonour R, Boswell HS. Novel combination treatments targeting chronic myeloid leukemia stem cells. Clin Lymphoma Myeloma Leuk. 2012;12:94\u2013105. https:\/\/doi.org\/10.1016\/j.clml.2011.10.003.","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"1363_CR12","doi-asserted-by":"publisher","first-page":"25476","DOI":"10.1038\/srep25476","volume":"6","author":"DA Irvine","year":"2016","unstructured":"Irvine DA, Zhang B, Kinstrie R, Tarafdar A, Morrison H, Campbell VL, et al. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep. 2016;6:25476. https:\/\/doi.org\/10.1038\/srep25476.","journal-title":"Sci Rep."},{"key":"1363_CR13","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1182\/blood.V101.2.690","volume":"101","author":"NJ Donato","year":"2003","unstructured":"Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, et al. BCR::ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101:690\u20138. https:\/\/doi.org\/10.1182\/blood.V101.2.690.","journal-title":"Blood"},{"key":"1363_CR14","doi-asserted-by":"publisher","first-page":"734","DOI":"10.18632\/aging.100821","volume":"7","author":"D Elias","year":"2015","unstructured":"Elias D, Ditzel HJ. The potential of Src inhibitors. Aging (Albany NY). 2015;7:734. https:\/\/doi.org\/10.18632\/aging.100821.","journal-title":"Aging (Albany. NY)"},{"key":"1363_CR15","doi-asserted-by":"publisher","first-page":"3767","DOI":"10.1182\/blood-2013-05-501460","volume":"122","author":"B Laperrousaz","year":"2013","unstructured":"Laperrousaz B, Jeanpierre S, Sagorny K, Voeltzel T, Ramas S, Kaniewski B, et al. Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression. Blood. 2013;122:3767\u201377. https:\/\/doi.org\/10.1182\/blood-2013-05-501460.","journal-title":"Blood"},{"key":"1363_CR16","doi-asserted-by":"publisher","first-page":"2860","DOI":"10.1182\/blood-2017-08-801019","volume":"130","author":"E Grockowiak","year":"2017","unstructured":"Grockowiak E, Laperrousaz B, Jeanpierre S, Voeltzel T, Guyot B, Gobert S, et al. Immature CML cells implement a BMP autocrine loop to escape TKI treatment. Blood. 2017;130:2860\u201371. https:\/\/doi.org\/10.1182\/blood-2017-08-801019.","journal-title":"Blood"},{"key":"1363_CR17","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/s41419-018-0905-2","volume":"9","author":"P Toofan","year":"2018","unstructured":"Toofan P, Busch C, Morrison H, O\u2019Brien S, J\u00f8rgensen H, Copland M, et al. Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal. Cell Death Dis. 2018;9:927. https:\/\/doi.org\/10.1038\/s41419-018-0905-2.","journal-title":"Cell Death Dis"},{"key":"1363_CR18","doi-asserted-by":"publisher","first-page":"715","DOI":"10.18632\/oncotarget.990","volume":"4","author":"JM Gerber","year":"2013","unstructured":"Gerber JM, Gucwa JL, Esopi D, Gurel M, Haffner MC, Vala M, et al. Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. Oncotarget. 2013;4:715. https:\/\/doi.org\/10.18632\/oncotarget.990.","journal-title":"Oncotarget"},{"key":"1363_CR19","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1517\/13543784.2010.499898","volume":"19","author":"S Schenone","year":"2010","unstructured":"Schenone S, Brullo C, Musumeci F, Botta M. Novel dual Src\/Abl inhibitors for hematologic and solid malignancies. Expert Opin Investig Drugs. 2010;19:931. https:\/\/doi.org\/10.1517\/13543784.2010.499898.","journal-title":"Expert Opin Investig Drugs"},{"key":"1363_CR20","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.molonc.2009.01.002","volume":"3","author":"TP Green","year":"2009","unstructured":"Green TP, Fennell M, Whittaker R, Curwen J, Jacobs V, Allen J, et al. Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol Oncol. 2009;3:248\u201361. https:\/\/doi.org\/10.1016\/j.molonc.2009.01.002.","journal-title":"Mol Oncol"},{"key":"1363_CR21","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s42003-019-0420-8","volume":"2","author":"D Carvalho","year":"2019","unstructured":"Carvalho D, Taylor KR, Olaciregui NG, Molinari V, Clarke M, Mackay A, et al. ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma. Commun Biol. 2019;2:156. https:\/\/doi.org\/10.1038\/s42003-019-0420-8.","journal-title":"Commun Biol"},{"issue":"8","key":"1363_CR22","doi-asserted-by":"publisher","first-page":"e95042","DOI":"10.1172\/jci.insight.95042","volume":"6","author":"E Williams","year":"2021","unstructured":"Williams E, Bagarova J, Kerr G, Xia DD, Place ES, Dey D, et al. Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight. 2021;6(8):e95042. https:\/\/doi.org\/10.1172\/jci.insight.95042.","journal-title":"JCI Insight"},{"key":"1363_CR23","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1124\/pr.58.3.10","volume":"58","author":"TC Chou","year":"2006","unstructured":"Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58:621\u201381. https:\/\/doi.org\/10.1124\/pr.58.3.10.","journal-title":"Pharmacol Rev"},{"key":"1363_CR24","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","volume":"70","author":"TC Chou","year":"2010","unstructured":"Chou TC. Drug combination studies and their synergy quantification using the chou-talalay method. Cancer Res. 2010;70:440\u20136. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-1947.","journal-title":"Cancer Res"},{"key":"1363_CR25","doi-asserted-by":"publisher","first-page":"14672","DOI":"10.1038\/s41598-018-33055-0","volume":"8","author":"TE Mulholland","year":"2018","unstructured":"Mulholland TE, McAllister M, Patek S, Flint D, Underwood M, Sim A, et al. Drug screening of biopsy-derived spheroids using a self-generated microfluidic concentration gradient. Sci Rep. 2018;8:14672. https:\/\/doi.org\/10.1038\/s41598-018-33055-0.","journal-title":"Sci Rep"},{"key":"1363_CR26","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1111\/j.1365-2818.2006.01706.x","volume":"224","author":"S Bolte","year":"2006","unstructured":"Bolte S, Cordeli\u00e8res FP. A guided tour into subcellular colocalization analysis in light microscopy. J Microsc. 2006;224:213\u201332. https:\/\/doi.org\/10.1111\/j.1365-2818.2006.01706.x.","journal-title":"J Microsc"},{"key":"1363_CR27","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1182\/blood.v99.1.319","volume":"99","author":"SM Graham","year":"2002","unstructured":"Graham SM, J\u00f8rgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319\u201325. https:\/\/doi.org\/10.1182\/blood.v99.1.319.","journal-title":"Blood"},{"key":"1363_CR28","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545\u201350. https:\/\/doi.org\/10.1073\/pnas.0506580102.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1363_CR29","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/ng1180","volume":"34","author":"VK Mootha","year":"2003","unstructured":"Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1\u03b1-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267\u201373. https:\/\/doi.org\/10.1038\/ng1180.","journal-title":"Nat Genet"},{"key":"1363_CR30","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon A, Birger C, Thorvaldsd\u00f3ttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417\u201325. https:\/\/doi.org\/10.1016\/j.cels.2015.12.004.","journal-title":"Cell Syst"},{"key":"1363_CR31","doi-asserted-by":"publisher","first-page":"6735","DOI":"10.1158\/0008-5472.CAN-16-1120","volume":"76","author":"JC Santos","year":"2016","unstructured":"Santos JC, Carrasco-Garcia E, Garcia-Puga M, Aldaz P, Montes M, Fernandez-Reyes M, et al. SOX9 elevation acts with canonical WNT signaling to drive gastric cancer progression. Cancer Res. 2016;76:6735\u201346. https:\/\/doi.org\/10.1158\/0008-5472.CAN-16-1120.","journal-title":"Cancer Res"},{"key":"1363_CR32","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1200\/JCO.2015.64.8899","volume":"34","author":"JE Cortes","year":"2016","unstructured":"Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqu\u00e9 C, et al. Final 5-year study results of DASISION: The dasatinib versus imatinib study in treatment-Na\u00efve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333\u201340. https:\/\/doi.org\/10.1200\/JCO.2015.64.8899.","journal-title":"J Clin Oncol"},{"key":"1363_CR33","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1038\/leu.2016.5","volume":"30","author":"A Hochhaus","year":"2016","unstructured":"Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044\u201354. https:\/\/doi.org\/10.1038\/leu.2016.5.","journal-title":"Leukemia"},{"key":"1363_CR34","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1182\/blood-2013-02-483750","volume":"122","author":"D Ross","year":"2013","unstructured":"Ross D, Branford S, Seymour J, Schwarer A, Arthur C, Yeung D, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122:515\u201322. https:\/\/doi.org\/10.1182\/blood-2013-02-483750.","journal-title":"Blood"},{"key":"1363_CR35","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1200\/JCO.2016.68.2914","volume":"35","author":"G Etienne","year":"2017","unstructured":"Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, et al. Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2017;35:298\u2013305. https:\/\/doi.org\/10.1200\/JCO.2016.68.2914.","journal-title":"J Clin Oncol"},{"key":"1363_CR36","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/S1470-2045(18)30192-X","volume":"19","author":"S Saussele","year":"2018","unstructured":"Saussele S, Richter J, Guilhot J, Gruber F, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19:747\u201357. https:\/\/doi.org\/10.1016\/S1470-2045(18)30192-X.","journal-title":"Lancet Oncol"},{"issue":"3","key":"1363_CR37","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1080\/10428194.2019.1675879","volume":"61","author":"NP Shah","year":"2020","unstructured":"Shah NP, Garc\u00eda-Guti\u00e9rrez V, Jim\u00e9nez-Velasco A, Larson S, Saussele S, Rea D, et al. Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study. Leuk Lymphoma. 2020;61(3):650\u20139. https:\/\/doi.org\/10.1080\/10428194.2019.1675879.","journal-title":"Leuk Lymphoma"},{"issue":"6","key":"1363_CR38","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1038\/s41375-021-01260-y","volume":"35","author":"TP Hughes","year":"2021","unstructured":"Hughes TP, Clementino NCD, Fominykh M, Lipton JH, Turkina AG, Moiraghi EB, et al. Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update. Leukemia. 2021;35(6):1631\u201342. https:\/\/doi.org\/10.1038\/s41375-021-01260-y.","journal-title":"Leukemia"},{"key":"1363_CR39","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1001\/jamaoncol.2020.5774","volume":"7","author":"E Atallah","year":"2021","unstructured":"Atallah E, Schifer CA, Radich JP, Weinfurt KP, Zhang MJ, Pinilla-Ibarz J, et al. Assessment of outcomes after stopping tyrosine kinase inhibitors among patients with chronic myeloid leukemia: a nonrandomized clinical trial. JAMA Oncol. 2021;7:42\u201350. https:\/\/doi.org\/10.1001\/jamaoncol.2020.5774.","journal-title":"JAMA Oncol"},{"issue":"10","key":"1363_CR40","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1002\/ajh.24120","volume":"90","author":"S Mori","year":"2015","unstructured":"Mori S, Vagge E, le Coutre P, Abruzzese E, Martino B, Pungolino E, et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015;90(10):910\u20134. https:\/\/doi.org\/10.1002\/ajh.24120.","journal-title":"Am J Hematol"},{"key":"1363_CR41","doi-asserted-by":"publisher","first-page":"e375","DOI":"10.1016\/S2352-3026(19)30094-8","volume":"6","author":"RE Clark","year":"2019","unstructured":"Clark RE, Polydoros F, Apperley JF, Milojkovic D, Rothwell K, Pocock C, et al. De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol. 2019;6:e375\u201383. https:\/\/doi.org\/10.1016\/S2352-3026(19)30094-8.","journal-title":"Lancet Haematol"},{"key":"1363_CR42","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1007\/s11899-021-00653-1","volume":"16","author":"E Atallah","year":"2021","unstructured":"Atallah E, Sweet K. Treatment-free remission: the new goal in CML therapy. Curr Hematol Malig Rep. 2021;16:433\u20139. https:\/\/doi.org\/10.1007\/s11899-021-00653-1.","journal-title":"Curr Hematol Malig Rep"},{"key":"1363_CR43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3324\/haematol.2019.232793","volume":"105","author":"S Jeanpierre","year":"2020","unstructured":"Jeanpierre S, Arizkane K, Thongjuea S, Grockowiak E, Geistlich K, Barral L, et al. The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission. Haematologica. 2020;105:1\u201321. https:\/\/doi.org\/10.3324\/haematol.2019.232793.","journal-title":"Haematologica"},{"key":"1363_CR44","doi-asserted-by":"publisher","first-page":"5766","DOI":"10.1093\/emboj\/cdf562","volume":"21","author":"A Klejman","year":"2002","unstructured":"Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, et al. The Src family kinase Hck couples BCR\/ABL to STAT5 activation in myeloid leukemia cells. EMBO J. 2002;21:5766\u201374. https:\/\/doi.org\/10.1093\/emboj\/cdf562.","journal-title":"EMBO J"},{"key":"1363_CR45","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1182\/blood-2002-01-0288","volume":"101","author":"M Warmuth","year":"2003","unstructured":"Warmuth M, Simon N, Mitina O, Mathes R, Fabbro D, Manley PW, et al. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant BCR::ABL kinases. Blood. 2003;101:664\u201372. https:\/\/doi.org\/10.1182\/blood-2002-01-0288.","journal-title":"Blood"},{"key":"1363_CR46","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1126\/scitranslmed.aag1180","volume":"8","author":"BZ Carter","year":"2016","unstructured":"Carter BZ, Mak PY, Mu H, Zhou H, Mak DH, Schober W, et al. Combined targeting of BCL-2 and BCR::ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med. 2016;8:355. https:\/\/doi.org\/10.1126\/scitranslmed.aag1180.","journal-title":"Sci Transl Med"},{"key":"1363_CR47","doi-asserted-by":"publisher","first-page":"5283","DOI":"10.1002\/cncr.27568","volume":"118","author":"A Quint\u00e1s-Cardama","year":"2012","unstructured":"Quint\u00e1s-Cardama A, Qiu YH, Post SM, Zhang Y, Creighton CJ, Cortes J, et al. Reverse phase protein array profiling reveals distinct proteomic signatures associated with chronic myeloid leukemia progression and with chronic phase in the CD34-positive compartment. Cancer. 2012;118:5283\u201392. https:\/\/doi.org\/10.1002\/cncr.27568.","journal-title":"Cancer"},{"key":"1363_CR48","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1038\/nature03669","volume":"435","author":"F Michor","year":"2005","unstructured":"Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL, et al. Dynamics of chronic myeloid leukaemia. Nature. 2005;435:1267\u201370. https:\/\/doi.org\/10.1038\/nature03669.","journal-title":"Nature"},{"key":"1363_CR49","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1182\/blood-2010-12-326843","volume":"119","author":"A Hamilton","year":"2015","unstructured":"Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on BCR::ABL kinase activity for their survival. Blood. 2015;119:1501\u201311. https:\/\/doi.org\/10.1182\/blood-2010-12-326843.","journal-title":"Blood"},{"key":"1363_CR50","doi-asserted-by":"publisher","first-page":"13790","DOI":"10.1038\/s41598-018-31696-9","volume":"8","author":"K Chanoumidou","year":"2018","unstructured":"Chanoumidou K, Hadjimichael C, Athanasouli P, Ahlenius H, Klonizakis A, Nikolaou C, et al. Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions. Sci Rep. 2018;8:13790. https:\/\/doi.org\/10.1038\/s41598-018-31696-9.","journal-title":"Sci Rep"},{"key":"1363_CR51","doi-asserted-by":"publisher","first-page":"676","DOI":"10.4161\/cbt.3.7.1026","volume":"3","author":"HC Huang","year":"2004","unstructured":"Huang HC, Klein PS. Interactions between BMP and Wnt signaling pathways in mammalian cancers. Cancer Biol Ther. 2004;3:676\u20138. https:\/\/doi.org\/10.4161\/cbt.3.7.1026.","journal-title":"Cancer Biol Ther"},{"key":"1363_CR52","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.tranon.2019.01.003","volume":"12","author":"PL Azevedo","year":"2019","unstructured":"Azevedo PL, Oliveira NC, Corr\u00eaa S, Castelo-Branco MT, Abdelhay E, Binato R. Canonical WNT signaling pathway is altered in Mesenchymal stromal cells from acute myeloid leukemia patients and is implicated in BMP4 down-regulation. Transl Oncol. 2019;12:614\u201325. https:\/\/doi.org\/10.1016\/j.tranon.2019.01.003.","journal-title":"Transl Oncol"},{"key":"1363_CR53","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.bone.2012.09.029","volume":"52","author":"R Zhang","year":"2013","unstructured":"Zhang R, Oyajobi BO, Harris SE, Chen D, Tsao C, Deng HW, et al. Wnt\/\u03b2-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone. 2013;52:145\u201356. https:\/\/doi.org\/10.1016\/j.bone.2012.09.029.","journal-title":"Bone"},{"key":"1363_CR54","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/S0301-472X(01)00612-9","volume":"29","author":"SM Garrido","year":"2001","unstructured":"Garrido SM, Appelbaum FR, Willman CL, Banker DE. Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). Exp Hematol. 2001;29:448\u201357. https:\/\/doi.org\/10.1016\/S0301-472X(01)00612-9.","journal-title":"Exp Hematol"},{"key":"1363_CR55","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41598-017-10373-3","volume":"7","author":"A Kumar","year":"2017","unstructured":"Kumar A, Bhattacharyya J, Jaganathan BG. Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways. Sci Rep. 2017;7:285\u201393. https:\/\/doi.org\/10.1038\/s41598-017-10373-3.","journal-title":"Sci Rep"},{"key":"1363_CR56","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/sj.cdd.4401279","volume":"10","author":"FH Paraguass\u00fa-Braga","year":"2003","unstructured":"Paraguass\u00fa-Braga FH, Borojevic R, Bouzas LF, Barcinski MA, Bonomo A. Bone marrow stroma inhibits proliferation and apoptosis in leukemic cells through gap junction-mediated cell communication. Cell Death Differ. 2003;10:1101\u20138. https:\/\/doi.org\/10.1038\/sj.cdd.4401279.","journal-title":"Cell Death Differ"},{"key":"1363_CR57","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1038\/sj.leu.2404489","volume":"21","author":"R Ramasamy","year":"2007","unstructured":"Ramasamy R, Lam EW, Soeiro I, Tisato V, Bonnet D, Dazzi F. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: Impact on in vivo tumor growth. Leukemia. 2007;21:304\u201310. https:\/\/doi.org\/10.1038\/sj.leu.2404489.","journal-title":"Leukemia"},{"issue":"Suppl","key":"1363_CR58","doi-asserted-by":"publisher","first-page":"11842","DOI":"10.1073\/pnas.2034201100","volume":"100","author":"E Passegu\u00e9","year":"2003","unstructured":"Passegu\u00e9 E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA. 2003;100(Suppl):11842\u20139. https:\/\/doi.org\/10.1073\/pnas.2034201100.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1363_CR59","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.beha.2006.10.005","volume":"20","author":"CT Jordan","year":"2007","unstructured":"Jordan CT. The leukemic stem cell. Best Pract Res Clin Haematol. 2007;20:13\u20138. https:\/\/doi.org\/10.1016\/j.beha.2006.10.005.","journal-title":"Best Pract Res Clin Haematol"},{"issue":"9","key":"1363_CR60","doi-asserted-by":"publisher","first-page":"4978","DOI":"10.1021\/acs.jmedchem.0c00395","volume":"63","author":"D Ensan","year":"2020","unstructured":"Ensan D, Smil D, Zepeda-Vel\u00e1zquez CA, Panagopoulos D, Wong JF, Williams EP, et al. Targeting ALK2: an open science approach to developing therapeutics for the treatment of diffuse intrinsic pontine glioma. J Med Chem. 2020;63(9):4978\u201396. https:\/\/doi.org\/10.1021\/acs.jmedchem.0c00395.","journal-title":"J Med Chem"},{"key":"1363_CR61","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.cytogfr.2009.10.021","volume":"20","author":"CC Hong","year":"2009","unstructured":"Hong CC, Yu PB. Applications of small molecule BMP inhibitors in physiology and disease. Cytokine Growth Factor Rev. 2009;20:409\u201318. https:\/\/doi.org\/10.1016\/j.cytogfr.2009.10.021.","journal-title":"Cytokine Growth Factor Rev"}],"container-title":["Cell Communication and Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-023-01363-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-023-01363-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-023-01363-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T04:04:41Z","timestamp":1701230681000},"score":1,"resource":{"primary":{"URL":"https:\/\/biosignaling.biomedcentral.com\/articles\/10.1186\/s12964-023-01363-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,29]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["1363"],"URL":"https:\/\/doi.org\/10.1186\/s12964-023-01363-2","relation":{},"ISSN":["1478-811X"],"issn-type":[{"value":"1478-811X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,29]]},"assertion":[{"value":"4 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Normal and CML samples were taken at diagnosis following informed consent in accordance with the Declaration of Helsinki, and the Greater Glasgow and Clyde National Health Service Ethical Approval (15\/WS\/0077).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"M.Z. is CEO of the company ScreenIn3D. The other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"342"}}