Arsenic trioxide and all-trans retinoic acid suppress the expression of FLT3-ITD

Abstract

The prognosis of patients with acute myeloid leukemia (AML) caused by the FLT3-ITD mutation is poor. Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) can down-regulate FLT3-ITD level and selectively kill leukemia cells carrying the FLT3-ITD mutation. However, the mechanisms of action of these two compounds are unknown. Here, we found that ATO could bind FLT3-ITD at Lys91 and Asp225, whereas ATRA could bind FLT3-ITD at Lys5 and Gln6. Both compounds could not bind wild-type FLT3. Further studies revealed that ATO/ATRA may suppress the Expression of FLT3-ITD by promoting the UBE2L6-mediated ubiquitination pathway and decreasing the expression of C-MYC. However, further studies are needed to define the mechanisms of these compounds on AML. Our research provides an experimental basis for the use of ATO/ATRA in FLT3-ITD AML in clinical practice.

Keywords:

• Degradation
• acute myeloid leukemia
• FLT3-ITD
• all-trans-retinoic acid
• arsenic trioxide

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This study was supported by the National Science Foundation of China [Grant No. 81600111 and 81600112], the Natural Science Foundation of Guangdong Province China [Grant No.2017A030313456], the Science and Technology Planning Project of Guangdong Province, China [Grant No.2017A020215186 and 2016A020215045], the Medical Science and Technology Foundation of Guangdong Province, China [Grant No. A2019400 and A2019375], the Science and Technology Planning Project of Guangzhou, China [Grant No. 201707010004, 201604020128 and 201607010326].