Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in acute myeloid leukemia.
Blood Adv
; 5(23): 5041-5046, 2021 12 14.
Article
em En
| MEDLINE
| ID: mdl-34614509
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Blood Adv
Ano de publicação:
2021
Tipo de documento:
Article