title: Tyrosinekinase inhibition facilitates cooperation of transcription factor SALL4 and ABC transporter A3 towards intrinsic CML cell drug resistance.
abstract: Although BCR-ABL1 tyrosine kinase inhibitors reliably induce disease remission for patients with chronic myeloid leukaemia (CML), unlimited extension of therapy is necessary to prevent relapse from persistent leukaemic cells. Here, we analysed model cell lines and primary CML cells for the expression and functions of the ABC transporter A3 (ABCA3) as well as the embryonic stem cell-associated transcription factor SALL4. ABCA3 protected leukaemic cells from the cytotoxic effects of the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. In the surviving cells, exposure to tyrosine kinase inhibitors significantly enhanced ABCA3 expression in vivo and in vitro, and was associated with increased expression of SALL4, which binds the ABCA3 promoter. Inhibition of ABCA3 or SALL4 by genetic silencing or indomethacin, but not interferon gamma, interrupted SALL4-dependent regulation of ABCA3 and restored susceptibility of leukaemic cells to tyrosine kinase inhibition. Tyrosine kinase inhibitor exposure facilitates a protective loop of SALL4 and ABCA3 cooperation in persistent leukaemic cells.
authors: Department of Haematology and Oncology, Georg-August-University Goettingen, Goettingen, Germany.
authors: Timo
authors: T
authors: Hupfeld
authors: Bjoern
authors: B
authors: Chapuy
authors: Verena
authors: V
authors: Schrader
authors: Markus
authors: M
authors: Beutler
authors: Christian
authors: C
authors: Veltkamp
authors: Raphael
authors: R
authors: Koch
authors: Silke
authors: S
authors: Cameron
authors: Thiha
authors: T
authors: Aung
authors: Detlef
authors: D
authors: Haase
authors: Paul
authors: P
authors: Larosee
authors: Lorenz
authors: L
authors: Truemper
authors: Gerald G
authors: GG
authors: Wulf
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C472575:SALL4 protein, human; D013844:Thiazoles; D014157:Transcription Factors; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib