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.
