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

Abstract

SummaryAlthough 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.

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

“…may also converge: the ABC transporter A3 contributes to drug sequestration in late endosomal organelles, that is, multivesicular bodies and lysosomes, as described by us and others for acute myeloid leukemia, chronic myeloid leukemia, and lung cancer cells (13,14,17,24,30,37,38). Here, we extend the evidence for vesicular export of anthracycline type drugs to aggressive lymphoma cells, and document the compaction of such drugs in exosomes.…”

“…3A). We and others recently identified the cyclooxygenase inhibitor indomethacin as a drug resistance modulator (16,(27)(28)(29) with suppression of ABCA3 expression on the transcriptional level (16,28,30). Importantly, indomethacin cotreatment almost completely diminished the doxorubicin-induced increase in ABCA3 expression after doxorubicin ( Fig.…”

SALL4: An emerging cancer biomarker and target

“…In addition to AML patients, constitutive expression of SALL4 has also been observed in CML cells in the blast crisis or accelerated phase. Exposure to tyrosine kinase inhibitors (TKI) leads to increased expression of SALL4 in CML cells, which consequently upregulates ABCA3 [39]. High ABCA3 levels facilitate detoxification of TKI, protecting CML cells against TKI effects.…”

Secretomics identifies follistatin as a predictive biomarker for response to treatment with tyrosine kinase inhibitors in synovial sarcoma

“…ROR1 was previously reported to sustain signaling for multiple receptor tyrosine kinases and overcome TKI resistance in non-small cell lung cancers 43) . Hupfeld et al reported that TK inhibition facilitates cooperation of transcription factor SALL4 and ATP-binding cassette transporters A3 in eliciting drug resistance in intrinsic chronic myelogenous leukemia cells 44) . CD24 contributes to resistance to lapatinib in HER2-positive breast cancer cells 45) .…”