Low-dose sorafenib combined with all-trans retinoic acid induces differentiation of acute myeloid leukemia cells with wild type Fms like tyrosine kinase 3

doi:10.16138/j.1673-6087.2022.06.002

Abstract

Abstract:

Objective To explore the effect and the mechanisms of the combination of low-dose sorafenib and all-tran retinoic acid (ATRA) in acute myeloid leukemia (AML) cells with wild type Fms like tyrosine kinase 3 (FLT3). Methods The wild type FLT3 AML cell lines HL-60, U937 and the ATRA-resistant HL-60 cell line, HL-60Res were used as in vitro models. The cell differentiation was evaluated with cell surface differentiation antigen CD11b and cellular morphology. The activation of Raf, mitogenactivated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), the protein expression levels of PU.1, C/EBPβ and C/EBPε were measured by Western blotting assay. Results Low dose (0.1~0.5 μmol/L) sorafenib enhanced ATRA-induced differentiation in all three cell lines studied. The combination activated Raf, MEK and ERK, and up-regulated the levels of C/EBPβ, C/EBPε and PU.1. Addition of trametinib, a MEK specific inhibitor, suppressed the differentiation induced by sorafenib and ATRA, preventing the activation of MEK/ERK and up-regulation of the levels of C/EBPβ, C/EBPε and PU.1. Conclusions The combination of low-dose sorafenib and ATRA induced differentiation of AML cells with wild type FLT3 via RAF/MEK/ERK-mediated up-regulation of the protein levels of C/EBPβ, C/EBPε and PU.1.

Key words: Sorafenib, All-trans retinoic acid, Differentiation, Acute myeloid leukemia

CLC Number:

R733.71

LU Hao, XI Huimin, LI Lu, CAI Xun. Low-dose sorafenib combined with all-trans retinoic acid induces differentiation of acute myeloid leukemia cells with wild type Fms like tyrosine kinase 3[J]. Journal of Internal Medicine Concepts & Practice, 2022, 17(06): 428-434.

Figures/Tables 5

References 25

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