{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:11:59Z","timestamp":1792757519801,"version":"4.5.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T00:00:00Z","timestamp":1653609600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T00:00:00Z","timestamp":1653609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium\/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    , and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.\n                  <\/jats:p>","DOI":"10.1038\/s41375-022-01606-0","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T08:02:31Z","timestamp":1653638551000},"page":"1990-2001","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Regulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication"],"prefix":"10.1038","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9478-2194","authenticated-orcid":false,"given":"Cheuk-Him","family":"Man","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy C. C.","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsz-Ho","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenny C. C.","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W. Y.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson K. L.","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-701X","authenticated-orcid":false,"given":"Stephen S. Y.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chae-Yin","family":"Cher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9975-8687","authenticated-orcid":false,"given":"Anskar Y. H.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"1606_CR1","doi-asserted-by":"publisher","first-page":"4077","DOI":"10.1182\/blood-2010-04-277269","volume":"116","author":"LD Cripe","year":"2010","unstructured":"Cripe LD, Uno H, Paietta EM, Litzow MR, Ketterling RP, Bennett JM, et al. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood. 2010;116:4077\u201385.","journal-title":"Blood."},{"key":"1606_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00425-3","volume":"11","author":"H Kantarjian","year":"2021","unstructured":"Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11:41.","journal-title":"Blood Cancer J"},{"key":"1606_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-020-00373-4","volume":"10","author":"SP Tsui","year":"2020","unstructured":"Tsui SP, Ip HW, Saw NY, Zhang C, Cheung AK, Ng NK, et al. Redefining prognostication of de novo cytogenetically normal acute myeloid leukemia in young adults. Blood Cancer J. 2020;10:104.","journal-title":"Blood Cancer J"},{"key":"1606_CR4","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.1056\/NEJMc1711824","volume":"377","author":"RM Stone","year":"2017","unstructured":"Stone RM, Larson RA, Dohner H. Midostaurin in FLT3-mutated acute myeloid leukemia. N Engl J Med. 2017;377:1903.","journal-title":"N Engl J Med"},{"key":"1606_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2016.51","volume":"6","author":"CY Cher","year":"2016","unstructured":"Cher CY, Leung GM, Au CH, Chan TL, Ma ES, Sim JP, et al. Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome. Blood Cancer J. 2016;6:e442.","journal-title":"Blood Cancer J"},{"key":"1606_CR6","doi-asserted-by":"publisher","first-page":"2968","DOI":"10.1111\/jcmm.14927","volume":"24","author":"E Weisberg","year":"2020","unstructured":"Weisberg E, Meng C, Case AE, Tiv HL, Gokhale PC, Buhrlage SJ, et al. Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia. J Cell Mol Med. 2020;24:2968\u201380.","journal-title":"J Cell Mol Med"},{"key":"1606_CR7","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1182\/blood.V95.4.1427.004k48_1427_1434","volume":"95","author":"IN Rich","year":"2000","unstructured":"Rich IN, Worthington-White D, Garden OA, Musk P. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)\/H(+) exchanger. Blood. 2000;95:1427\u201334.","journal-title":"Blood."},{"key":"1606_CR8","doi-asserted-by":"publisher","first-page":"2530","DOI":"10.1182\/blood-2013-07-512194","volume":"123","author":"CH Man","year":"2014","unstructured":"Man CH, Lam SS, Sun MK, Chow HC, Gill H, Kwong YL, et al. A novel tescalcin-sodium\/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML. Blood. 2014;123:2530\u20139.","journal-title":"Blood."},{"key":"1606_CR9","doi-asserted-by":"publisher","first-page":"5591","DOI":"10.1158\/0008-5472.CAN-17-0764","volume":"77","author":"VL Payen","year":"2017","unstructured":"Payen VL, Hsu MY, Radecke KS, Wyart E, Vazeille T, Bouzin C, et al. Monocarboxylate transporter MCT1 promotes tumor metastasis independently of its activity as a lactate transporter. Cancer Res. 2017;77:5591\u2013601.","journal-title":"Cancer Res"},{"key":"1606_CR10","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1158\/1535-7163.MCT-17-0535","volume":"17","author":"HK Kim","year":"2018","unstructured":"Kim HK, Lee I, Bang H, Kim HC, Lee WY, Yun SH, et al. MCT4 expression is a potential therapeutic target in colorectal cancer with peritoneal carcinomatosis. Mol Cancer Ther. 2018;17:838\u201348.","journal-title":"Mol Cancer Ther"},{"key":"1606_CR11","doi-asserted-by":"crossref","unstructured":"Man CH, Mercier FE, Liu N, Dong W, Stephanopoulos G, Jiang L, et al. Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive hematopoietic progenitor growth. Blood. 2022;139:502\u201322.","DOI":"10.1182\/blood.2021011563"},{"key":"1606_CR12","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5397-7","volume":"19","author":"Q Chen","year":"2019","unstructured":"Chen Q, Liu Y, Zhu XL, Feng F, Yang H, Xu W. Increased NHE1 expression is targeted by specific inhibitor cariporide to sensitize resistant breast cancer cells to doxorubicin in vitro and in vivo. BMC Cancer. 2019;19:211.","journal-title":"BMC Cancer"},{"key":"1606_CR13","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1002\/ijc.25009","volume":"127","author":"A De Milito","year":"2010","unstructured":"De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, et al. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer. 2010;127:207\u201319.","journal-title":"Int J Cancer"},{"key":"1606_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70396-1","volume":"10","author":"N Piasentin","year":"2020","unstructured":"Piasentin N, Milotti E, Chignola R. The control of acidity in tumor cells: a biophysical model. Sci Rep. 2020;10:13613.","journal-title":"Sci Rep"},{"key":"1606_CR15","doi-asserted-by":"crossref","unstructured":"Toft NJ, Axelsen TV, Pedersen HL, Mele M, Burton M, Balling E, et al. Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival. Elife. 2021;10:e68447.","DOI":"10.7554\/eLife.68447"},{"key":"1606_CR16","doi-asserted-by":"publisher","first-page":"400","DOI":"10.3389\/fphys.2013.00400","volume":"4","author":"O Sedlakova","year":"2014","unstructured":"Sedlakova O, Svastova E, Takacova M, Kopacek J, Pastorek J, Pastorekova S. Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors. Front Physiol. 2014;4:400.","journal-title":"Front Physiol"},{"key":"1606_CR17","doi-asserted-by":"publisher","first-page":"e0207417","DOI":"10.1371\/journal.pone.0207417","volume":"13","author":"MY Mboge","year":"2018","unstructured":"Mboge MY, Chen Z, Wolff A, Mathias JV, Tu C, Brown KD, et al. Selective inhibition of carbonic anhydrase IX over carbonic anhydrase XII in breast cancer cells using benzene sulfonamides: disconnect between activity and growth inhibition. PLoS One. 2018;13:e0207417.","journal-title":"PLoS One"},{"key":"1606_CR18","doi-asserted-by":"publisher","first-page":"28274","DOI":"10.1074\/jbc.M702373200","volume":"282","author":"J Luo","year":"2007","unstructured":"Luo J, Kintner DB, Shull GE, Sun D. ERK1\/2-p90RSK-mediated phosphorylation of Na+\/H+ exchanger isoform 1. A role in ischemic neuronal death. J Biol Chem. 2007;282:28274\u201384.","journal-title":"J Biol Chem"},{"key":"1606_CR19","doi-asserted-by":"publisher","first-page":"26666","DOI":"10.1074\/jbc.M109.019448","volume":"284","author":"ME Meima","year":"2009","unstructured":"Meima ME, Webb BA, Witkowska HE, Barber DL. The sodium-hydrogen exchanger NHE1 is an Akt substrate necessary for actin filament reorganization by growth factors. J Biol Chem. 2009;284:26666\u201375.","journal-title":"J Biol Chem"},{"key":"1606_CR20","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1158\/0008-5472.CAN-12-4031","volume":"73","author":"SR Amith","year":"2013","unstructured":"Amith SR, Fliegel L. Regulation of the Na+\/H+ Exchanger (NHE1) in breast cancer metastasis. Cancer Res. 2013;73:1259\u201364.","journal-title":"Cancer Res"},{"key":"1606_CR21","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1083\/jcb.200908086","volume":"188","author":"M Koivusalo","year":"2010","unstructured":"Koivusalo M, Welch C, Hayashi H, Scott CC, Kim M, Alexander T, et al. Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J Cell Biol. 2010;188:547\u201363.","journal-title":"J Cell Biol"},{"key":"1606_CR22","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/nature10334","volume":"478","author":"J Zuber","year":"2011","unstructured":"Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;478:524\u20138.","journal-title":"Nature."},{"key":"1606_CR23","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.ccr.2011.06.010","volume":"20","author":"KM Bernt","year":"2011","unstructured":"Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell. 2011;20:66\u201378.","journal-title":"Cancer Cell"},{"key":"1606_CR24","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.yjmcc.2013.02.007","volume":"61","author":"S Wakabayashi","year":"2013","unstructured":"Wakabayashi S, Hisamitsu T, Nakamura TY. Regulation of the cardiac Na(+)\/H(+) exchanger in health and disease. J Mol Cell Cardiol. 2013;61:68\u201376.","journal-title":"J Mol Cell Cardiol"},{"key":"1606_CR25","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.cellsig.2015.01.002","volume":"27","author":"MA Wallert","year":"2015","unstructured":"Wallert MA, Hammes D, Nguyen T, Kiefer L, Berthelsen N, Kern A, et al. RhoA Kinase (Rock) and p90 Ribosomal S6 Kinase (p90Rsk) phosphorylation of the sodium hydrogen exchanger (NHE1) is required for lysophosphatidic acid-induced transport, cytoskeletal organization and migration. Cell Signal. 2015;27:498\u2013509.","journal-title":"Cell Signal"},{"key":"1606_CR26","doi-asserted-by":"publisher","first-page":"20206","DOI":"10.1074\/jbc.274.29.20206","volume":"274","author":"E Takahashi","year":"1999","unstructured":"Takahashi E, Abe J, Gallis B, Aebersold R, Spring DJ, Krebs EG, et al. p90(RSK) is a serum-stimulated Na+\/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+\/H+ exchanger isoform-1. J Biol Chem. 1999;274:20206\u201314.","journal-title":"J Biol Chem"},{"key":"1606_CR27","doi-asserted-by":"publisher","first-page":"6292","DOI":"10.1074\/jbc.M611073200","volume":"282","author":"ME Malo","year":"2007","unstructured":"Malo ME, Li L, Fliegel L. Mitogen-activated protein kinase-dependent activation of the Na+\/H+ exchanger is mediated through phosphorylation of amino acids Ser770 and Ser771. J Biol Chem. 2007;282:6292\u20139.","journal-title":"J Biol Chem"},{"key":"1606_CR28","doi-asserted-by":"publisher","first-page":"7545","DOI":"10.1128\/MCB.21.22.7545-7557.2001","volume":"21","author":"AR Khaled","year":"2001","unstructured":"Khaled AR, Moor AN, Li A, Kim K, Ferris DK, Muegge K, et al. Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Mol Cell Biol. 2001;21:7545\u201357.","journal-title":"Mol Cell Biol"},{"key":"1606_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06445-z","volume":"7","author":"AC Alves","year":"2017","unstructured":"Alves AC, Magarkar A, Horta M, Lima J, Bunker A, Nunes C, et al. Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies. Sci Rep. 2017;7:6343.","journal-title":"Sci Rep"},{"key":"1606_CR30","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1056\/NEJMra1406184","volume":"373","author":"H Dohner","year":"2015","unstructured":"Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136\u201352.","journal-title":"N Engl J Med"},{"key":"1606_CR31","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1200\/JCO.2016.71.2208","volume":"35","author":"L Bullinger","year":"2017","unstructured":"Bullinger L, Dohner K, Dohner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35:934\u201346.","journal-title":"J Clin Oncol"},{"key":"1606_CR32","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","volume":"368","author":"N Cancer Genome Atlas Research","year":"2013","unstructured":"Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059\u201374.","journal-title":"N Engl J Med"},{"key":"1606_CR33","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1182\/blood-2013-06-511154","volume":"123","author":"SA Rushworth","year":"2014","unstructured":"Rushworth SA, Murray MY, Zaitseva L, Bowles KM, MacEwan DJ. Identification of Bruton\u2019s tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood. 2014;123:1229\u201338.","journal-title":"Blood."},{"key":"1606_CR34","doi-asserted-by":"publisher","first-page":"9930","DOI":"10.18632\/oncotarget.2479","volume":"5","author":"L Zaitseva","year":"2014","unstructured":"Zaitseva L, Murray MY, Shafat MS, Lawes MJ, MacEwan DJ, Bowles KM, et al. Ibrutinib inhibits SDF1\/CXCR4 mediated migration in AML. Oncotarget. 2014;5:9930\u20138.","journal-title":"Oncotarget."},{"key":"1606_CR35","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1182\/blood-2014-06-585216","volume":"125","author":"T Oellerich","year":"2015","unstructured":"Oellerich T, Mohr S, Corso J, Beck J, Dobele C, Braun H, et al. FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation. Blood. 2015;125:1936\u201347.","journal-title":"Blood."},{"key":"1606_CR36","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1038\/s41375-020-0764-6","volume":"34","author":"CA Eide","year":"2020","unstructured":"Eide CA, Kurtz SE, Kaempf A, Long N, Agarwal A, Tognon CE, et al. Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia. Leukemia. 2020;34:2342\u201353.","journal-title":"Leukemia."},{"key":"1606_CR37","doi-asserted-by":"crossref","unstructured":"Morell A, Cermakova L, Novotna E, Lastovickova L, Haddad M, Haddad A, et al. Bruton\u2019s tyrosine kinase inhibitors ibrutinib and acalabrutinib counteract anthracycline resistance in cancer cells expressing AKR1C3. Cancers (Basel). 2020;12:3731.","DOI":"10.3390\/cancers12123731"},{"key":"1606_CR38","doi-asserted-by":"publisher","first-page":"e35949","DOI":"10.1371\/journal.pone.0035949","volume":"7","author":"P Swietach","year":"2012","unstructured":"Swietach P, Hulikova A, Patiar S, Vaughan-Jones RD, Harris AL. Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS One. 2012;7:e35949.","journal-title":"PLoS One"},{"key":"1606_CR39","doi-asserted-by":"publisher","first-page":"9643","DOI":"10.1158\/0008-5472.CAN-05-0422","volume":"65","author":"CH Brandts","year":"2005","unstructured":"Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005;65:9643\u201350.","journal-title":"Cancer Res"},{"key":"1606_CR40","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/onc.2017.376","volume":"37","author":"Q Heydt","year":"2018","unstructured":"Heydt Q, Larrue C, Saland E, Bertoli S, Sarry JE, Besson A, et al. Oncogenic FLT3-ITD supports autophagy via ATF4 in acute myeloid leukemia. Oncogene. 2018;37:787\u201397.","journal-title":"Oncogene."},{"key":"1606_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-58651-x","volume":"10","author":"G Sueur","year":"2020","unstructured":"Sueur G, Boutet A, Gotanegre M, Mansat-De Mas V, Besson A, Manenti S, et al. STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia. Sci Rep. 2020;10:1906.","journal-title":"Sci Rep"},{"key":"1606_CR42","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-019-0148-9","volume":"8","author":"C Larrue","year":"2019","unstructured":"Larrue C, Heydt Q, Saland E, Boutzen H, Kaoma T, Sarry JE, et al. Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia. Oncogenesis. 2019;8:39.","journal-title":"Oncogenesis."},{"key":"1606_CR43","doi-asserted-by":"crossref","unstructured":"Khoury JD, Tashakori M, Yang H, Loghavi S, Wang Y, Wang J, et al. Pan-RAF inhibition shows anti-leukemic activity in RAS-mutant acute myeloid leukemia cells and potentiates the effect of sorafenib in cells with FLT3 mutation. Cancers (Basel). 2020;12:3511.","DOI":"10.3390\/cancers12123511"},{"key":"1606_CR44","doi-asserted-by":"crossref","unstructured":"Cabral JM, Gracio D, Soares-da-Silva P, Magro F. Short- and long-term regulation of intestinal Na+\/H+ exchange by toll-like receptors TLR4 and TLR5. Am J Physiol Gastrointest Liver Physiol. 2015;309:G703\u201315.","DOI":"10.1152\/ajpgi.00124.2015"},{"key":"1606_CR45","doi-asserted-by":"publisher","first-page":"5133","DOI":"10.1182\/blood-2011-06-363960","volume":"119","author":"CH Man","year":"2012","unstructured":"Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC, et al. Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012;119:5133\u201343.","journal-title":"Blood."},{"key":"1606_CR46","doi-asserted-by":"publisher","first-page":"8957","DOI":"10.1128\/JVI.77.16.8957-8951.2003","volume":"77","author":"M Wiznerowicz","year":"2003","unstructured":"Wiznerowicz M, Trono D. Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol. 2003;77:8957\u201361.","journal-title":"J Virol"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01606-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01606-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01606-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T05:08:24Z","timestamp":1659330504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01606-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,27]]},"references-count":46,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["1606"],"URL":"https:\/\/doi.org\/10.1038\/s41375-022-01606-0","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,27]]},"assertion":[{"value":"14 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 May 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}