Blocking DNA Damage Repair May Be Involved in Stattic (STAT3 Inhibitor)-Induced FLT3-ITD AML Cell Apoptosis.

Yuxuan Luo,Yanling Yang,Xiangzhong Zhang,Yansi Lin,Bing Long,Jingwen Zhang,Ying Lu,Yichuang Xu

doi:10.3389/fcell.2021.637064

Abstract

The FMS-like tyrosine kinase 3 (FLT3)- internal tandem duplication (ITD) mutation can be found in approximately 25% of all acute myeloid leukemia (AML) cases and is associated with a poor prognosis. The main treatment for FLT3-ITD-positive AML patients includes genotoxic therapy and FLT3 inhibitors, which are rarely curative. Inhibiting STAT3 activity can improve the sensitivity of solid tumor cells to radiotherapy and chemotherapy. This study aimed to explore whether Stattic (a STAT3 inhibitor) affects FLT3-ITD AML cells and the underlying mechanism. Stattic can inhibit the proliferation, promote apoptosis, arrest cell cycle at G0/G1, and suppress DNA damage repair in MV4-11cells. During the process, through mRNA sequencing, we found that DNA damage repair-related mRNA are also altered during the process. In summary, the mechanism by which Stattic induces apoptosis in MV4-11cells may involve blocking DNA damage repair machineries.

Highlights

FMS-like tyrosine kinase 3 (FLT3) mutations include the FLT3-internal tandem duplication (ITD) mutation and FLT3-tyrosine kinase domain mutation
The MV4-11 cell line is often used in the study of FLT3-ITD mutant acute myeloid leukemia (AML)
The results showed that the FLT3 sequences of KG1a and HL60 cell lines were consistent with those of the wildtype, whereas FLT3 of MV4-11 cells had an inserted 30 base pair sequence (Figure 1)

Summary

Introduction

FMS-like tyrosine kinase 3 (FLT3) mutations include the FLT3-internal tandem duplication (ITD) mutation (approximately 25% of all AML cases) and FLT3-tyrosine kinase domain mutation (approximately 7–10% of all AML cases). FLT3-ITD is a common driver mutation that presents a high leukemic burden and is associated with a poor prognosis in patients with AML (Daver et al, 2019). The FLT3-ITD mutation is the insertion of a repetitive segment of the gene encoding the membrane region of the FLT3 receptor. The MV4-11 cell line is a FLT3-ITD mutant leukemia cell line which is often used in research related to FLT3-ITD AML (Quentmeier et al, 2003). Previous studies have found that in FLT3-ITD AML cells, there is high spontaneous DNA damage and both the micro-homologymediated alternative non-homologous end-joining (Alt-NHEJ) and homologous recombination (HR) pathways are active (Fan et al, 2010). Alt-NHEJ is error-prone and leads to gene mutations

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