CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia

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.

Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene

“…Moreover additional genes were downregulated by the treatment with GANT61 ( p  < 0.05), as for example, genes involved in cell cycle control, such as CDC25A , CDC7 , CDCA2 , and CCNA2 . The expression of these genes is required for progression through cell cycle, and their expression is aberrant in AML, as well as in other malignancies [9, 10]. In our model, the expression of these genes is downregulated following GANT61 treatment, this partly explaining the cell cycle arrest observed in AML cell lines with GLIS2 fusion after GANT61 treatment (Fig.…”

Targeting Tyrosine Phosphatases: Time to End the Stigma

“…administration of IRC-083864 inhibited pancreatic carcinoma tumor growth[35]. Recently, IRC-083864 was shown to inhibit clonogenic capacity of primary acute myeloid leukemia (AML) cells expressing the transforming Fms-like tyrosine kinase 3 internal tandem duplication[36]. IRC-083864 was licensed by Debiopharm Group as Debio 0931 for clinical development.…”

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

“…FLT3-ITD activates STAT5, PI3-kinase/AKT and MAP-kinase signaling pathways [5]. Each of these pathways has an impact on the G1/S transition, through control of the cell cycle regulators [6, 7]. …”