Changes of signal transductivity and robustness of gene regulatory network in the carcinogenesis of leukemic subtypes via microarray sample data.

Cheng-Wei Li,Tzu-Ying Lai,Bor-Sen Chen

doi:10.18632/oncotarget.25318

Abstract

Mutation accumulation and epigenetic alterations in genes are important for carcinogenesis. Because leukemogenesis-related signal pathways have been investigated and microarray sample data have been produced in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and normal cells, systems analysis in coupling pathways becomes possible.Based on system modeling and identification, we could construct the coupling pathways and their associated gene regulatory networks using microarray sample data. By applying system theory to the estimated system model in coupling pathways, we can then obtain transductivity sensitivity, basal sensitivity and error sensitivity of each protein to identify the potential impact of genetic mutations, epigenetic alterations and the coupling of other pathways from the perspective of energy, respectively. By comparing the results in AML, MDS and normal cells, we investigated the potential critical genetic mutations and epigenetic alterations that activate or repress specific cellular functions to promote MDS or AML leukemogenesis. We suggested that epigenetic modification of β-catenin and signal integration of CSLs, AP-2α, STATs, c-Jun and β-catenin could contribute to cell proliferation at AML and MDS. Epigenetic regulation of ERK and genetic mutation of p53 could lead to the repressed apoptosis, cell cycle arrest and DNA repair in leukemic cells. Genetic mutation of JAK, epigenetic regulation of ERK, and signal integration of C/EBPα could result in the promotion of MDS cell differentiation. According to the results, we proposed three drugs, decitabine, genistein, and monorden for preventing AML leukemogenesis, while three drugs, decitabine, thalidomide, and geldanamycin, for preventing MDS leukemogenesis.

Highlights

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid neoplasms
In this study we define the transductivity sensitivity, basal sensitivity, and error sensitivity of each protein in signal transduction pathways (STPs) to suggest the dysregulated proteins in STPs leading to AML/ MDS leukemogenesis and the potential leukemogenesis from MDS to AML from the perspective of energy transportation based on genetic and epigenetic changes
For the intrinsic variations, including the molecular alteration and genetic and epigenetic changes, in the nucleus, we suggested that the gene regulatory networks (GRNs) in the patients with AML and MDS would harbor more variations to drive the diversity and progression of leukemic cells during leukemogenesis

Summary

Introduction

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid neoplasms. Gene expression analysis in leukemic cells including MDS and AML has revealed that hematopoietic stem cells (HSCs) are regulated for self-renewal ability, quiescence and differentiation [1]. In oncogenesis and leukemogenesis, according to the 2-hit hypothesis mutations, genes involved in various signal transduction pathways (STPs), such as the MAPK, PI3K-AKT, NF-κB, JAK-STAT pathways, can disrupt the dynamic balance between apoptosis, cell survival, and proliferation [1,2,3]. STPs mediate signal amplification (or attenuation) of cellular microenvironment signals to alter cellular function through transcriptional regulations. Intrinsic variations, such as genetic mutations www.oncotarget.com and epigenetic regulations, would perturb transcriptional regulations to influence cellular responses

Methods

Results

Discussion

Conclusion