Trametinib enhances ATRA-induced differentiation in AML cells

Abstract

All-trans retinoic acid (ATRA) is only clinically useful in acute promyelocytic leukemia (APL), but not other subtypes of acute myeloid leukemia (AML). In the present study, a clinically achievable concentration of trametinib, a highly selective inhibitor of MEK, enhanced ATRA-induced differentiation in AML cell lines, HL-60 and U937 as well as AML primary cells. Moreover, trametinib–ATRA (tra–ATRA) co-treatment restored ATRA sensitivity in ATRA-resistant AML cell line, HL-60Res. The protein level of STAT3 and the phosphorylation of Akt or JNK were enhanced with tra–ATRA treatment in HL-60, U937, and HL-60Res cells, respectively. Furthermore, tra–ATRA-induced differentiation in HL-60, U937, and HL-60Res cells was inhibited by STAT3, PI3K, and JNK inhibitors, respectively. Therefore, STAT3, Akt, and JNK signaling pathways were involved in tra–ATRA-induced differentiation in HL-60, U937, and HL-60Res cells, respectively. Taken together, our findings may provide novel therapeutic strategies for AML patients.

Keywords:

• Acute myeloid leukemia
• trametinib
• all-trans retinoic acid
• differentiation

Disclosure statement

The authors declare that they have no competing interests.

Author contributions

H L, ZY L, M D, L C, XQ W, Y S, and J W carried out the experiments. H L and ZY L prepared all the figures. X C designed the study and wrote the manuscript. All authors read and approved the final manuscript.

Additional information

Funding

This work is supported by the Natural Science Foundation of Shanghai under Grant 17ZR1417100.