FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia

Blood. 2020 Apr 23;135(17):1472-1483. doi: 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-ITD+ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tandem Repeat Sequences
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Up-Regulation
  • Xenograft Model Antitumor Assays
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

  • Biomarkers, Tumor
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Protein Kinase Inhibitors
  • Repressor Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • HDAC8 protein, human
  • Histone Deacetylases