Tyrosinekinase inhibition facilitates cooperation of transcription factor SALL4 and ABC transporter A3 towards intrinsic CML cell drug resistance

• DOI: 10.1111/bjh.12246
• Publication Date: 2013-02-21T17:58:36Z
• Authors: Timo Hupfeld; Bjoern Chapuy; Verena Schrader; Markus Beutler; Christian Veltkamp; Raphael Koch; Silke Cameron; Thiha Aung; Detlef Haase; Paul LaRosee; Lorenz Truemper; Gerald G. Wulf
• Keywords: Male; Gene Expression Regulation, Leukemic; Dasatinib; HL-60 Cells; Piperazines; Neoplasm Proteins; 3. Good health; Mice; Thiazoles; 03 medical and health sciences; Pyrimidines; 0302 clinical medicine; Drug Resistance, Neoplasm; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Benzamides; Imatinib Mesylate; Animals; Humans; ATP-Binding Cassette Transporters; Female; K562 Cells; Protein Kinase Inhibitors; Transcription Factors

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 the expression functions ABC transporter A3 (ABCA3) as well embryonic stem cell-associated transcription factor SALL4. ABCA3 protected cytotoxic effects imatinib, dasatinib, nilotinib. In surviving cells, exposure significantly enhanced in vivo vitro, was associated increased SALL4, which binds promoter. Inhibition or SALL4 by genetic silencing indomethacin, but not interferon gamma, interrupted SALL4-dependent regulation restored susceptibility inhibition. Tyrosine inhibitor facilitates a protective loop cooperation