Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in acute myeloid leukemia
| Autor: | Megan E. Zavorka Thomas, Navjot Pabla, Daelynn R. Buelow, Sharyn D. Baker, Alex Sparreboom, Jae Yoon Jeon, Josie A. Silvaroli, Moray J. Campbell, Zahra Talebi |
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| Rok vydání: | 2021 |
| Předmět: |
Aniline Compounds
medicine.drug_class Myeloid leukemia Hematology Drug resistance Biology BCL6 S100A9 Tyrosine-kinase inhibitor Up-Regulation Leukemia Myeloid Acute Downregulation and upregulation Pyrazines hemic and lymphatic diseases Proto-Oncogene Proteins c-bcl-6 Cancer research medicine Humans Receptor Transcription factor |
| Zdroj: | Blood Advances. 5:5041-5046 |
| ISSN: | 2473-9537 2473-9529 |
| DOI: | 10.1182/bloodadvances.2021005614 |
| Popis: | Drug resistance and relapse are common challenges in acute myeloid leukemia (AML), particularly in an aggressive subset bearing internal tandem duplications (ITDs) of the FLT3 receptor (FLT3-ITD+). The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet resistance to gilteritinib remains a clinical concern, and the underlying mechanisms remain incompletely understood. Using transcriptomic analyses and functional validation studies, we identified the calcium-binding proteins S100A8 and S100A9 (S100A8/A9) as contributors to gilteritinib resistance in FLT3-ITD+ AML. Exposure of FLT3-ITD+ AML cells to gilteritinib increased S100A8/A9 expression in vivo and in vitro and decreased free calcium levels, and genetic manipulation of S100A9 was associated with altered sensitivity to gilteritinib. Using a transcription factor screen, we identified the transcriptional corepressor BCL6, as a regulator of S100A9 expression and found that gilteritinib decreased BCL6 binding to the S100A9 promoter, thereby increasing S100A9 expression. Furthermore, pharmacological inhibition of BCL6 accelerated the growth rate of gilteritinib-resistant FLT3-ITD+ AML cells, suggesting that S100A9 is a functional target of BCL6. These findings shed light on mechanisms of resistance to gilteritinib through regulation of a target that can be therapeutically exploited to enhance the antileukemic effects of gilteritinib. |
| Databáze: | OpenAIRE |
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