Abstract
We investigated cell cycle regulation in acute myeloid leukemia cells expressing the FLT3-ITD mutated tyrosine kinase receptor, an underexplored field in this disease. Upon FLT3 inhibition, CDC25A mRNA and protein were rapidly down-regulated, while levels of other cell cycle proteins remained unchanged. This regulation was dependent on STAT5, arguing for FLT3-ITD-dependent transcriptional regulation of CDC25A. CDC25 inhibitors triggered proliferation arrest and cell death of FLT3-ITD as well as FLT3-ITD/TKD AC-220 resistant cells, but not of FLT3-wt cells. Consistently, RNA interference-mediated knock-down of CDC25A reduced the proliferation of FLT3-ITD cell lines. Finally, the clonogenic capacity of primary FLT3-ITD AML cells was reduced by the CDC25 inhibitor IRC-083864, while FLT3-wt AML and normal CD34+ myeloid cells were unaffected. In good agreement, in a cohort of 100 samples from AML patients with intermediate-risk cytogenetics, high levels of CDC25A mRNA were predictive of higher clonogenic potential in FLT3-ITD+ samples, not in FLT3-wt ones.Importantly, pharmacological inhibition as well as RNA interference-mediated knock-down of CDC25A also induced monocytic differentiation of FLT3-ITD positive cells, as judged by cell surface markers expression, morphological modifications, and C/EBPα phosphorylation. CDC25 inhibition also re-induced monocytic differentiation in primary AML blasts carrying the FLT3-ITD mutation, but not in blasts expressing wild type FLT3. Altogether, these data identify CDC25A as an early cell cycle transducer of FLT3-ITD oncogenic signaling, and as a promising target to inhibit proliferation and re-induce differentiation of FLT3-ITD AML cells.
Highlights
Acute myeloid leukemia (AML) is characterized by increased proliferation and cell death resistance, and by a block of the hematopoietic process occurring at different stages of the myeloid differentiation [1]
We demonstrate that CDC25A is an early target of Fms-Like Tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) oncogenic signaling, and is an important player of AML cells proliferation and differentiation arrest
In order to identify links between the FLT3ITD mutated receptor and cell cycle progression, we investigated the expression of cell cycle regulating proteins upon FLT3-ITD inhibition in MV4-11 and MOLM-14, two AML cell lines carrying FLT3-ITD mutation
Summary
Acute myeloid leukemia (AML) is characterized by increased proliferation and cell death resistance, and by a block of the hematopoietic process occurring at different stages of the myeloid differentiation [1]. The impact of several mutations has been explored this last decade, one of the most frequent being the internal tandem duplication (ITD) in the juxta-membrane domain of the Fms-Like Tyrosine kinase 3 (FLT3), which leads to constitutive www.impactjournals.com/oncotarget activation of this receptor [2] This mutation is associated to normal karyotype [3] and takes part to the most recent prognostic classification of AML [4]. Because of the high frequency of this mutation (25– 30% of AML) and of its associated negative prognostic [3, 6], several FLT3 inhibitors have been developed and tested in different clinical trials, either as single agent or in combination with chemotherapy [7,8,9,10,11,12] These molecules have a negative impact on AML cells proliferation in vivo, and interestingly, their pro-differentiation effect was reported clinically, suggesting that inhibiting FLT3-ITD could partially relieve the differentiation arrest occurring in this category of AML [13]. Recent studies identified the ERK kinase and the cyclin-dependent kinase CDK1 as important players of FLT3-ITD AML differentiation arrest through phosphorylation of the C/EBPα transcription factor on its serine 21 [14,15,16], suggesting that CDK or ERK inhibitors could restore the differentiation program of these cells
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