Kinomics Screening Identifies Aberrant Phosphorylation of CDC25C in FLT3-ITD-positive AML

Abstract

Abstract. Background/Aim: The presence of FLT3-Internal tandem duplications (ITDs) in human acute myeloid leukemia (AML) is associated with a dismal prognosis. Altered cell-cycle activity has been reported in FLT3-ITD-positive AML; however, the mechanisms by which this oncogene influences cell-cycle activity remained so far elusive. Materials and MethodsAcute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal selection and accumulation of mutations during disease progression (1). FLT3 is one of the most frequently mutated genes in adult AML (2-4) that encodes for a receptor tyrosine kinase required for maintenance of normal hematopoiesis (5). During leukemia development, the occurrence of FLT3-internal tandem duplications (ITD) induces constitutive activation of the encoded receptor tyrosine kinase and leads to activation of downstream effectors, such as STAT5, ERK and AKT. Depending on cooperating oncogenic events, presence of FLT3-ITD may be associated with a poor prognosis in patients with AML (2, 6, 7). Recent reports also suggested that constitutive activation of FLT3-signaling might result in aberrant cell-cycle activity (8).Stringent regulation of cell-cycle activity is of major importance to ensure proper development of hematopoiesis and to orchestrate tissue regeneration. Conversely, deregulation of cell cycle-relevant proteins can promote the development of cancer (9, 10). The final steps during cell-cycle transition are controlled by cyclin-dependent kinases (CDKs) in complex with the appropriate cyclins. CDKs are preserved in an inactive state through phosphorylation of distinct amino acid residues. Several amino acid residues need to be dephosphorylated by cell division cycle 25 (CDC25) phosphatases (9, 10) to activate CDKs. Therefore, CDC25 phosphatases are essential regulators of cell cycle progression in malignant and non-malignant cells. In mammals, this group of phosphatases consists of three homologues, CDC25A, CDC25B and CDC25C. These are involved in pathogenesis of human malignancies (9, 10) and, specifically, myeloid leukemia (11, 12). While CDC25A is important for S-phase entry and, crucial for regulating cellular proliferation (13), CDC25B and CDC25C are believed to control mitosis entry (14). Taken together, all CDC25 phosphatases are involved in cell-cycle checkpoint regulation with redundant and non-redundant functions (9). Recently, frequent mutation of CDC25C has been reported in patients with familial platelet disorder (FPD). CDC25C defines a preleukemic clone, which eventually acquires additional mutations during disease progression. Of note, the observed CDC25C mutations are exclusively found in FPD patients rather than in de novo AML or myelodysplastic syndromes (MDSs) (15). Here, we provide first evidence that FLT3-ITD induces aberrant phosphorylation of CDC25C that functionally mimics features observed in the mutant CDC25C isoforms of FPD patients. 6249Τhis article is freely accessible online. ANTICANCER RESEARCH 36: 6249-6258 (2016) Mat...

Lamprey Prohibitin2 Arrest G2/M Phase Transition of HeLa Cells through Down-regulating Expression and Phosphorylation Level of Cell Cycle Proteins

“…It is well known that the loss of these checkpoints can lead to the transition and progression of cancer cells. CDC25C is responsible for stimulating and maintaining the complexes CCNB1-CDK1 activation that ultimately determines to pass the G2 checkpoint 25 . PLK1 also promotes G2/M transition progression through affecting the subcellular localization of CDK1 regulatory checkpoint nodes.…”

Selection of Protein Kinase Inhibitors Based on Tumor Tissue Kinase Activity Profiles in Patients with Refractory Solid Malignancies: An Interventional Molecular Profiling Study

“…A particular clinical need exists for tools to enable selection of multitargeted PKIs and for patients with advanced solid tumors refractory to standard treatment, who could benefit from repurposing of available drugs. Several potentially useful tumor‐profiling platforms such as peptide and (reverse phase) protein microarrays have been suggested to infer kinase activity for treatment stratification or target identification . Preclinical and clinical data have shown some indications that a 144‐tyrosine kinase peptide substrate microarray may be of value for treatment selection .…”

How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia

“…Stronger phosphorylation signals were found in FLT3-ITD-mutated AML patients with higher ITD lengths [29]. Aberrant cell-death signaling through receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and upregulation of anti-apoptotic myeloid cell leukemia-1 (MCL-1), aberrant cell-cycle regulation, among others through CDC25A and CDC25C, and aberrant oncogenic signaling through phosphorylation of cytokine receptor common subunit beta (CSF2RB) were detected in FLT3-ITD-mutated cells [30][31][32][33][34][35]. Furthermore, FLT3-ITD mediates metabolic effects leading to the upregulation of aerobic glycolysis and cell-extrinsic effects by affecting dendritic cells and T cells [36,37].…”