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Article: A novel tescalcin-sodium/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML

TitleA novel tescalcin-sodium/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML
Authors
Issue Date2014
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2014, v. 123 n. 16, p. 2530-2539 How to Cite?
AbstractInternal tandem duplication (ITD) of fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is associated with inferior clinical prognosis. Sorafenib is effective in clearing leukemic blasts in chemorefractory FLT3-ITD+ AML, but leukemia progression invariably occurs. Mechanisms of drug resistance are not completely understood. We hypothesized that a gene encoding tescalcin (TESC), known to be upregulated at leukemia progression during continuous sorafenib treatment and activate an Na+/H+ exchanger type-1 (NHE1), may underlie tyrosine kinase inhibitor resistance. TESC was highly expressed in FLT3-ITD+ AML lines MOLM-13 and MV4-11, and its knockdown by small-interfering RNA lowered intracellular pH (pHi) and induced apoptosis. The results were recapitulated by treatment with an NHE1 inhibitor, 5-(N,N-hexamethylene) amiloride (HMA). Induction of sorafenib resistance in the MOLM-13 cell line (M13-RE) significantly increased its sensitivity to HMA. The later also enhanced suppression of FLT3 signaling by sorafenib in otherwise resistant cell lines. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD+ AML cells significantly reduced leukemia initiation in anti-CD122-primed NOD/SCID mouse xenotransplantation. These observations provided novel information about the pathogenetic role of a TESC-NHE1-pHi axis in mediating sorafenib resistance in AML.
Persistent Identifierhttp://hdl.handle.net/10722/200695
ISSN
2019 Impact Factor: 17.543
2015 SCImago Journal Rankings: 6.395
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMan, CH-
dc.contributor.authorLam, SSY-
dc.contributor.authorSun, MKH-
dc.contributor.authorChow, HCH-
dc.contributor.authorSingh, GHH-
dc.contributor.authorKwong, YL-
dc.contributor.authorLeung, AYH-
dc.date.accessioned2014-08-21T06:55:35Z-
dc.date.available2014-08-21T06:55:35Z-
dc.date.issued2014-
dc.identifier.citationBlood, 2014, v. 123 n. 16, p. 2530-2539-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/200695-
dc.description.abstractInternal tandem duplication (ITD) of fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is associated with inferior clinical prognosis. Sorafenib is effective in clearing leukemic blasts in chemorefractory FLT3-ITD+ AML, but leukemia progression invariably occurs. Mechanisms of drug resistance are not completely understood. We hypothesized that a gene encoding tescalcin (TESC), known to be upregulated at leukemia progression during continuous sorafenib treatment and activate an Na+/H+ exchanger type-1 (NHE1), may underlie tyrosine kinase inhibitor resistance. TESC was highly expressed in FLT3-ITD+ AML lines MOLM-13 and MV4-11, and its knockdown by small-interfering RNA lowered intracellular pH (pHi) and induced apoptosis. The results were recapitulated by treatment with an NHE1 inhibitor, 5-(N,N-hexamethylene) amiloride (HMA). Induction of sorafenib resistance in the MOLM-13 cell line (M13-RE) significantly increased its sensitivity to HMA. The later also enhanced suppression of FLT3 signaling by sorafenib in otherwise resistant cell lines. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD+ AML cells significantly reduced leukemia initiation in anti-CD122-primed NOD/SCID mouse xenotransplantation. These observations provided novel information about the pathogenetic role of a TESC-NHE1-pHi axis in mediating sorafenib resistance in AML.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.titleA novel tescalcin-sodium/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML-
dc.typeArticle-
dc.identifier.emailMan, CH: csman729@hku.hk-
dc.identifier.emailSingh, GHH: gillhsh@hku.hk-
dc.identifier.emailKwong, YL: ylkwong@hku.hk-
dc.identifier.emailLeung, AYH: ayhleung@hku.hk-
dc.identifier.authorityMan, CH=rp02543-
dc.identifier.authoritySingh, GHH=rp01914-
dc.identifier.authorityKwong, YL=rp00358-
dc.identifier.authorityLeung, AYH=rp00265-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1182/blood-2013-07-512194-
dc.identifier.pmid24608976-
dc.identifier.scopuseid_2-s2.0-84901826874-
dc.identifier.hkuros233893-
dc.identifier.volume123-
dc.identifier.issue16-
dc.identifier.spage2530-
dc.identifier.epage2539-
dc.identifier.isiWOS:000335894500020-
dc.publisher.placeUnited States-

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