<p>PRKD2 Promotes Progression and Chemoresistance of AML via Regulating Notch1 Pathway</p>

Abstract

Introduction: Progression and chemoresistance of acute myeloid leukemia (AML) contribute to most of the treatment failure. Notch pathway has been proven to be involved in many biological processes and diseases, especially AML. In this study, we aimed to explore genes correlated with Notch1 pathway in AML and determine their roles in the regulation of AML progression and chemoresistance. Methods: TCGA database was used to explore Notch1 associated genes. Kaplan-Meier survival analysis was performed to evaluate the prognostic significance of genes. Quantitative RT-PCR (qRT-PCR) and Western blot were performed to examine the expression of genes. The expression of PRKD2 was up-regulated or knocked down in AML cell lines by lentivirus or siRNAs. CCK-8 and flow cytometry were used to analyze the effect of PRKD2 on cell proliferation and chemoresistance. Results: Based on TCGA database, PRKD2 was found to be positively correlated with Notch1 expression, cytogenetic risk status and poorer prognosis in AML. Moreover, the expression level of PRKD2 was higher in AML chemo-resistant cells than in chemo-sensitive cells. Functionally, knockdown of PRKD2-induced apoptosis and increased chemosensitivity of AML cells. PRKD2 overexpression promoted proliferation and chemoresistance of AML cells. Furthermore, we found PRKD2 could regulate Notch1 pathway. Besides, high PRKD2 expression was correlated with higher risk group of AML patients which indicated that PRKD2 was an independent prognostic marker for AML. Conclusion: Taken together, our results showed that PRKD2 could promote the proliferation and chemoresistance of AML cells by regulating Notch1 pathway. The study broadened our insights into the underlying mechanisms in chemoresistance and proliferation of AML, and provided a new prognostic marker and treatment target for AML.

Regulatory Networks of Prognostic mRNAs in Pediatric Acute Myeloid Leukemia

“…Among them, the karyotype is of great value to prognostic judgment, and there are obviously different treatment responses in patients with the same or normal karyotype immediately [ 23 ]. Genetic detecting can not only effectively warn the occurrence and diagnosis of diseases, but also provide targeted therapeutic targets for clinical treatment [ 24 ]. In this study, through the analysis of gene expression and the overall survival of patients, we found as many as 11672 prognostic-related genes in AML patients.…”

MicroRNA‑181b‑5p insufficiency predicts treatment response failure risk and unfavorable event‑free survival as well as overall survival in acute myeloid leukemia patients

“…In this study, we discovered that miR-181b-5p expression was attenuated in AML patients. A possible reason might be that miR-181b-5p could regulate several leukemogenic signaling pathways, including Wnt, protein kinase B and Notch 1 pathways, which are correlated with the pathogenesis of AML (18)(19)(20)(21)(22)(23). Therefore, its expression was attenuated in the AML patients.…”

A zebrafish forward genetic screen identifies an indispensable threonine residue in the kinase domain of PRKD2

“…Moreover, PRKD2 expression has been correlated with key genes involved in Notch pathway in newly diagnosed acute myeloid leukemia (AML) patients ( Liu et al, 2019 ) and there is evidence that PRKD2 promotes proliferation and chemo-resistance of human AML cell lines through a mechanisms involving Notch activity ( Liu et al, 2019 ). Our observation that notch1b , bmp4 , and the flow responsive transcriptional factor klf2a (factors that have been implicated in AV valve formation) ( Kalogirou et al, 2014 ) are detected throughout the hearts of s411 mutants – these factors do not localize to the AV region – reinforces the notion that PRKD2 sits at a nodal point controlling a number of signaling pathways that regulate AV valve formation.…”