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Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in acute myeloid leukemia
| Content Provider | Scilit |
|---|---|
| Author | Thomas, Megan E. Zavorka Jeon, Jae Yoon Talebi, Zahra Buelow, Daelynn R. Silvaroli, Josie Campbell, Moray J. Sparreboom, Alex Pabla, Navjot Baker, Sharyn D. |
| Copyright Year | 2021 |
| Description | 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. |
| Related Links | https://ashpublications.org/bloodadvances/article-pdf/doi/10.1182/bloodadvances.2021005614/1826517/bloodadvances.2021005614.pdf |
| Ending Page | 5046 |
| Page Count | 6 |
| Starting Page | 5041 |
| DOI | 10.1182/bloodadvances.2021005614 |
| Journal | Blood advances |
| Issue Number | 23 |
| Volume Number | 5 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2021-12-03 |
| Access Restriction | Open |
| Subject Keyword | Research and Experimental Medicine Aml Transcription Factor S100a9 Functional Bcl6 Flt3 Itd Resistance To Gilteritinib Journal: Blood advances (Vol- 136, Issue- 23) |
| Content Type | Text |
| Resource Type | Article |
