title: A novel tescalcin-sodium/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML.
abstract: Internal 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.
authors.affiliation: Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Cheuk Him
authors.initials: CH
authors.lastname: Man
authors.forename: Stephen S Y
authors.initials: SS
authors.lastname: Lam
authors.forename: Murphy K H
authors.initials: MK
authors.lastname: Sun
authors.forename: Howard C H
authors.initials: HC
authors.lastname: Chow
authors.forename: Harinder
authors.initials: H
authors.lastname: Gill
authors.forename: Yok Lam
authors.initials: YL
authors.lastname: Kwong
authors.forename: Anskar Y H
authors.initials: AY
authors.lastname: Leung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D027682:Cation Transport Proteins / Q000502:physiology*; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*; D000077157:Sorafenib; D020080:Tandem Repeat Sequences / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D010671:Phenylurea Compounds; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C486009:TESC protein, human; D009536:Niacinamide; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3