Abstract
BackgroundAcute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes. All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) have resulted in durable cytogenetic and molecular remissions in most APL patients and have altered the natural history of the disease. Most APL patients treated with ATRA and/or ATO are now anticipated to have a nearly normal life expectancy. Unfortunately, relapse and resistance to the current treatment occur in APL patients and the outcome remains dismal in these refractory patients.AXL receptor tyrosine kinase (AXL-RTK) has been shown to increase tumour burden, provide resistance to therapy and is critical to maintain cancer stem cells (CSCs) in chronic myeloid leukemia (CML) by stabilizing β-catenin in the Wnt/β-catenin signalling pathway. However, the role of AXL-RTK has not been explored in PML/RARα-positive APL. This study aimed to explore the role of AXL-RTK receptor in PML/RARα-positive APL.Methods and resultsBy using biochemical and pharmacological approaches, here we report that targeting of AXL-RTK is related to the down-regulation of β-catenin target genes including c-myc (p < 0.001), AXIN2 (p < 0.001), and HIF1α (p < 0.01) and induction of apoptosis in PML/RARα-positive APL cell line. Resistance to all-trans retinoic acid (ATRA) was also overcomed by targeting AXL-RTK with R428 in APL (p < 0.05).ConclusionOur results provide clear evidence of the involvement of AXL-RTK in leukemogenic potential of PML/RARα-positive APL and suggest targeting of AXL-RTK in the treatment of therapy resistant APL patients.
Highlights
Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes
AXL receptor tyrosine kinase (AXL-receptor tyrosine kinases (RTKs)) inhibitor R428 was purchased from MedChem-Express, New Jersey, USA and dissolved in dimethyl sulfoxide (DMSO) (Sigma, Steinheim, Germany) to a 1000X stock solution, which were further diluted to 1X working concentrations for the experiments
Inhibition of AXL-RTK with R428 and PML/RARα with all-trans retinoic acid (ATRA) showed additive anti-proliferative effect in NB4 cells Our results show that AXL-RTK is up-regulated in NB4 cells and targeting AXL-RTK strongly interferes with the proliferation potential of NB4 cell line
Summary
Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes. Alltrans retinoic acid (ATRA) and/or arsenic trioxide (ATO) have resulted in durable cytogenetic and molecular remissions in most APL patients and have altered the natural history of the disease. The role of AXL-RTK has not been explored in PML/RARα-positive APL. This study aimed to explore the role of AXL-RTK receptor in PML/RARα-positive APL. About 80% of APL patients achieve complete remission when all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) are combined with conventional chemotherapy [4]. One of the important reasons of ATRA resistance is mutation in the ligand binding domain (LBD) of RARα which can be found in 40% of the relapse patients [5]. Resistance to ATO therapy is attributable to mutations in the B2-domain of PML/RARα which continues to pose a clinical challenge in APL patients [7]. Non-specificity of chemotherapy, inability of ATRA and ATO as alone or in combination for APL therapy, and arsenic poisoning [8] impel to seek other treatment options of APL
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