Differentiation resistance through altered retinoblastoma protein function in acute lymphoblastic leukemia: in silico modeling of the deregulations in the G1/S restriction point pathway

Eleftherios Ouzounoglou, Dimitra Dionysiou, Georgios S. Stamatakos

As in many cancer types, the G1/S restriction point (RP) is deregulated in Acute Lymphoblastic Leukemia (ALL). Hyper-phosphorylated retinoblastoma protein (hyper-pRb) is found in high levels in ALL cells. Nevertheless, the ALL lymphocyte proliferation rate for the average patient is surprisingly low compared to its normal counterpart of the same maturation level. Additionally, as stated in literature, ALL cells possibly reside at or beyond the RP which is located in the late-G1 phase. This state may favor their differentiation resistant phenotype. A major phenomenon contributing to this fact is thought to be the observed limited redundancy in the phosphorylation of retinoblastoma protein (pRb) by the various Cyclin Dependent Kinases (Cdks). The latter may result in partial loss of pRb functions despite hyper-phosphorylation. To test this hypothesis, an in silico model aiming at simulating the biochemical regulation of the RP in ALL is introduced. By exploiting experimental findings derived from leukemic cells and following a semi-quantitative calibration procedure, the model has been shown to satisfactorily reproduce such a behavior for the RP pathway. At the same time, the calibrated model has been proved to be in agreement with the observed variation in the ALL cell cycle duration. The proposed model aims to contribute to a better understanding of the complex phenomena governing the leukemic cell cycle. At the same time it constitutes a significant first step in the creation of a personalized proliferation rate predictor that can be used in the context of multiscale cancer modeling. Such an approach is expected to play an important role in the refinement and the advancement of mechanistic modeling of ALL in the context of the emergent and promising scientific domains of In Silico Oncology and more generally In Silico Medicine.