Pathway simulations in common oncogenic drivers of leukemic and rhabdomyosarcoma cells: A systems biology approach

Abstract

Abstract. A part of current research has intensively been focused on the proliferation and metabolic processes governing biological systems. Since the advent of high throughput methodologies such as microarrays, the load of genomic data has increased geometrically and along with that the need for computational methods to interpret these data. In the present study, we investigated in vitro the common proliferation and metabolic processes, associated with common oncogenic pathways, as far as gene expression is concerned, between the T-cell acute lymphoblastic leukemia (CCRF-CEM) and the rhabdomyosarcoma (TE-671) cell lines. We present a computational approach, using cDNA microarrays, in order to identify commonalities between diverse biological systems. Our analysis predicted that JAK1, STAT1, PIAS2 and CDK4 are the driving forces in the two cell lines. This type of analysis may lead to the understanding of the common mechanisms that transform physiological cells to malignant, and may reveal a new holistic approach to understanding the dynamics of tumor onset as well as the mechanistics behind oncogenic drivers. IntroductionIt is a fact that tumors can be as diverse as the patients carrying them. Due to these differences, tumors are extremely difficult to cure, as the effects of treatments differ depending on the patient. Previously, Nicolis showed that stem cells are found in different tumor types, suggesting that they can be the etiology of tumor maintenance and growth (1). However, there is evidence that even normal, already differentiated cells can be transformed into tumorigenic ones (1). Perilongo et al also reported a case of a child manifesting five different tumor types simultaneously (2). It may be possible that stem cells originating from the same organism possess similar mutations or alterations, thus giving rise to five different tumor types. Therefore, there is a need for the investigation of common pathways between different tumor types. The discovery of similar or opposite gene expression profiles could lead us to the understanding of a common tumor origin, if such exists.A number of studies have investigated the detection of cancer germ line genes (CGGs) both in pediatric sarcomas (3) and pediatric brain tumors (4). The discovery of global antigens for tumor vaccines could become salvatory for childhood malignancies (3). Other studies have reported the common appearance of antigens in Ewing's sarcoma/primitive neuroectodermal tumor (EWS/PNET) with lymphoblastic lymphoma (5). Rhabdomyosarcoma (RMS) belongs to the PNET family of tumors, which utilize embryonic genes for their progression (6). Acute lymphoblastic leukemia (ALL), which originates from the lymphoblast, also uses embryonic mechanisms for its differentiation and progression.Another point which requires attention is the regulation of genes through transcription factors (TFs). Knowledge of gene regulatory networks is considered to be of crucial importance for understanding diseases such as cancer, and may lead to new therapeutic approaches...

The functional diversity of essential genes required for mammalian cardiac development

“…The increasingly systematic nature of random mutagenesis and mutation identification, targeted mutagenesis/ cloning and identification of epigenetic modifications along with increasing computational power and variety of bioinformatic approaches are facilitating these efforts. Systems biological approaches can be used to model metabolic pathways, dynamics of specific cell behavior under varying stimuli, disease causing aberrations in functional networks and in screening for potential therapeutic agents (Chen et al, 2012;Lambrou et al, 2012;Nagasaki et al, 2011;Tan et al, 2013). These approaches can also demonstrate the consequences of nonsynonymous DNA polymorphisms on protein interactions and identify mutations leading to development of diseases (Reimand and Bader, 2013;Yates and Sternberg, 2013a).…”

Synchronous Occurance of Acute Myeloid Leukemia and Rhabdomyosarcoma

“…Synchronous occurrence of these cancers points to an underlying genetic event affecting two entirely different lineages. Review of literature revealed study comparing the expression profiles of Precursor T cell lymphoblastic leukemia and RMS cell lines and identified common oncogenic driving forces which were responsible for the progression of cancer cells [7]. Both muscle and hematopoietic stem cells arise from the embryonal mesoderm.…”

“…Both muscle and hematopoietic stem cells arise from the embryonal mesoderm. Further differentiation enables the two cell types to possess different functions and roles by differential gene regulation [7]. An early mutation occurring during embryonal development may predispose the individual for double malignancies involving the tissue types which develop from the mesoderm.…”

Signaling pathways that overactivate metabolism and drive neoplasia, in rhabdomyosarcoma

“…Finally, a computational approach, using cDNA microarrays, in order to identify commonalities between T-cell acute lymphoblastic leukemia (CCRF-CEM) and the embryonal rhabdomyosarcoma (TE-671) cell line predicted that JAK1, STAT1, PIAS2 and CDK4 are the driving forces that transform physiological cells to malignant 96 .…”