2. Academic Validation
  3. Trametinib enhances ATRA-induced differentiation in AML cells

Trametinib enhances ATRA-induced differentiation in AML cells

  • Leuk Lymphoma. 2021 Dec;62(14):3361-3372. doi: 10.1080/10428194.2021.1961231.
Hao Lu 1,  Ze-Yi Li 1,  Ming Ding 2,  Cui Liang 3,  Xiang-Qin Weng 1,  Yan Sheng 1,  Jing Wu 1,  Xun Cai 1
Affiliations

Affiliations

  • 1 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Hematology Oncology, Central Hospital of Minhang District, Shanghai, China.
  • 3 Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
PMID: 34355652 DOI: 10.1080/10428194.2021.1961231
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; all-trans retinoic acid; differentiation; trametinib.

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