Abstract
The somatic mutation of FLT3 occurs in 30% of acute myeloid leukemia (AML), with the majority of mutations exhibiting internal tandem duplication (ITD). On the other hand, the induction of telomerase reverse transcriptase (hTERT) and the activation of telomerase is a key step in AML development. Here, we sought to determine whether FLT3ITD regulates hTERT expression in AML cells and whether hTERT expression affects FLT3 inhibitors’ therapeutic efficacy on AML. FLT3ITD-harboring AML cell lines and primary cells treated with the FLT3 inhibitor PKC412 displayed a rapid decline in the levels of hTERT mRNA and telomerase activity. Moreover, PKC412 inhibited hTERT gene transcription in a c-MYC-dependent manner. The ectopic expression of hTERT significantly attenuated the apoptotic effect of PKC412 on AML cells. Mechanistically, hTERT enhanced the activity of FLT3 downstream effectors or alternative RTK signaling, thereby enhancing AKT phosphorylation, in AML cells treated with PKC412. Collectively, PKC412 downregulates hTERT expression and telomerase activity in a MYC-dependent manner and this effect is required for its optimal anti-AML efficacy, while hTERT over-expression confers AML cells resistance to a targeted therapeutic agent PKC412. These findings suggest that the functional interplay between FLT3ITD and hTERT contributes to the AML pathogenesis and interferes with the efficacy of FLT3ITD-targeted therapy.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies, characterized by a differentiation block and aberrant clonal growth of hematopoietic blasts, and results from specific recurrent cytogenetic abnormalities and somatic mutations
The study presented here shows that FLT3ITD is required for constitutive hTERT transcription and sustained telomerase activity in MOLM-13 and MV4,11 cells
Inhibiting FLT3ITD by a specific tyrosine kinase inhibitors (TKIs) PKC412 led to diminished hTERT expression and telomerase activity
Summary
Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies, characterized by a differentiation block and aberrant clonal growth of hematopoietic blasts, and results from specific recurrent cytogenetic abnormalities and somatic mutations. Many AML patients who receive FLT3TKIs eventually acquire drug resistance [5, 7,8,9] It has been well-characterized that the occurrence of new mutations in the FLT3 genome is an important mechanism contributing to patients’ resistance to FLT3TKIs [5, 7,8,9]. Such new mutations were only found in a fraction of patients who have developed FLT3TKI resistance, and there likely exist other elements affecting the therapeutic efficacy of FLT3TKIs [9,10,11,12]. Better understanding of the biological functions of FLT3ITD and of the
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