FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia
- 23 April 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 135 (17), 1472-1483
- https://doi.org/10.1182/blood.2019003538
Abstract
Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITDv AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase-activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.This publication has 50 references indexed in Scilit:
- Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanismsNature Communications, 2019
- FLT3 inhibition in acute myeloid leukaemiaThe Lancet Oncology, 2017
- Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysisBlood, 2017
- Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panelBlood, 2017
- Acute Myeloid LeukemiaThe New England Journal of Medicine, 2015
- Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemiaLeukemia, 2015
- Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid LeukemiaThe New England Journal of Medicine, 2013
- Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemiaNature, 2012
- FLT3 as a therapeutic target in AML: still challenging after all these yearsBlood, 2010
- Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathwaysBlood, 2006