A Molecular Systems Analysis of Hox PPI Networks in Hematopoiesis and Leukemogenesis

Abstract

Hox proteins play important development and regulatory roles in the body including that of hematopoiesis. Different effects on these Hox proteins result in different malignant phenotypes resulting from interaction with cofactors, other transcriptional factors, fusion proteins and other Hox genes. Identification of the most probable pathway was determined through use of Cytoscape 2.2.3 functions and plug-ins to derive Hox protein networks from selected protein interaction databases (HPRD, MINT and Cancer Cell Map) and biological literature databases related to leukemia (PubMed and OMIM), which were then integrated using Advanced network plugin vl.12. Subnetworks were generated using Cytoscape function whereas complexes were generated using MCODE. Overrepresented gene ontology terms of complexes and subnetworks were determined using BiNGO. The integrated network produced provides the most significant pathways that could be connected to Hox gene overexpression. Aberrant protein transcriptional factors and fusion proteins are probably the main source of leukemia type and subtype determination because of its direct connection to specific Hox genes, leading to varying phenotypes. Each of these Hox genes (H0XA7, H0XA9, HOXAIO, H0XB3, H0XB4 and H0XC8) performs various regulatory functions during expansion and differentiation of hematopoietic stem cells and is responsible for controlling specific stages of the myeloid and lymphocytic lineages. With altered functionalities related to mutated transcription factors, cofactors and the presence of fusion proteins, interconnected protein activity affects regulation of target Hox genes and connected Hox genes. Leukemia progresses due to abnormal novel combination of functions leading to uncontrolled hematopoietic activity resulting from Hox gene overexpression. Nevertheless, other leukemic therapies also rely on controlling these aberrant interactions through inhibition of genes that affect the modified functions.