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

• Published in: British journal of haematology Vol. 161; no. 2; pp. 204 - 213
• Main Authors: Hupfeld, Timo, Chapuy, Bjoern, Schrader, Verena, Beutler, Markus, Veltkamp, Christian, Koch, Raphael, Cameron, Silke, Aung, Thiha, Haase, Detlef, LaRosee, Paul, Truemper, Lorenz, Wulf, Gerald G.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01-04-2013
• Subjects: ABCA3; Animals; ATP-Binding Cassette Transporters - biosynthesis; Benzamides - pharmacology; Biological and medical sciences; chronic myeloid leukaemia; Dasatinib; Drug Resistance, Neoplasm - drug effects; Female; Gene Expression Regulation, Leukemic - drug effects; Hematologic and hematopoietic diseases; HL-60 Cells; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Mice; Neoplasm Proteins - metabolism; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; SALL4; Thiazoles - pharmacology; Transcription Factors - metabolism; Tumors; tyrosine kinase inhibition; Treatment resistance; Hematology; Enzyme; Transferases; ABCA3; Chronic myelogenous leukemia; tyrosine kinase inhibition; Malignant hemopathy; chronic myeloid leukaemia; Myeloproliferative syndrome; Signal transduction; Cancerology; Cooperation; SALL4; Inhibitor; Transcription factor; Protein-tyrosine kinase; ABC transporter; Cancer
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.12246

Summary
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.