Formal Modeling and Analysis of Cell Cycle Regulator E2F1 and Micro RNA-223 in Acute Myeloid Leukemia

Abstract

CCAAT enhancer binding protein alpha (C/EBPα), is a fundamental transcrip- tion factor for granulopoiesis (formation of granulocytes i.e. white blood cells)

but its expression is downregulated in leukemia. Downregulation of E2F1, the

expert controller of myeloid cell proliferation by C/EBP α is significant for granu- lopoiesis as it is involved in activation of microRNA-223 (miR-223). Latter studies

show that miR-223, a transcriptional focus of C/EBP α, acts as a discriminating player during granulopoiesis and is downregulated in distinctive subtypes of Acute Myeloid Leukemia. Discrete modeling formalism of Ren ́e Thomas is a well-known

methodology utilized for demonstration and examination of Biological Regula- tory Networks (BRNs). Logical parameters for the BRN were induced utilizing

Ren ́e Thomas formalism, executed in SMBioNet. Discrete modeling of the BRN

is further carried out to foresee behaviors which either prompt ordinary granu- locytic differentiation or differentiation blockage using GENOTECH tool. The

results obtained from GENOTECH suggest that out of 16 models, the models ob- tained from multivalued boolean logic (e.g. BRN named as 12121) provided better

results rather than models obtained from boolean formalism. Further on, the re- sults generated from these models suggest that downregulation of E2F1 because

of increased threshold levels of C/EBPα and miR-223 can lead towards normal granulopoiesis instead of uncontrolled proliferation (the myeloid cells). The delay constraints are computed by using hybrid model (Bio-Linear Hybrid Automaton) which characterize the homeostasis of the BRN. These findings suggest that E2F1 can be potential therapeutic target for AML.