Normal vs. Malignant hematopoiesis: the complexity of acute leukemia through systems biology
Development of normal hematopoietic cells is an ordered multi-step process, tightly regulated by a complex network of intrinsic factors and microenvironmental cues that control cell fate decisions within the bone marrow (BM) (Pelayo et al., 2012; Purizaca et al., 2012; Boulais and Frenette, 2015). During malignant hematological disorders, including acute leukemias (AL), the uncontrolled differentiation of precursors of the lymphoid or myeloid series sustains tumor growth at the expense of normal blood cell production. Moreover, selection and dominance among leukemic clones occur while competing for niche resources and creating abnormal BM microenvironments that co-participate in the pathobiology of the disease (Colmone et al., 2008; Ayala et al., 2009; Purizaca et al., 2012; Kim et al., 2015; Vilchis-Ordonez et al., 2015). Thus, due to the complexity and health impact of AL (Gupta et al., 2014), new strategies to better predict cell population dynamics according to genetics, microenvironmental and clinical heterogeneous contexts may contribute to understand its pathobiology and to guide strategies for decreasing overall mortality. Mathematical modeling has emerged as a powerful tool in biomedical and health research because it enables the simulation of complex biological systems and the efficient generation of testable hypotheses. In recent years, leukemic cell dynamics has been addressed from the novel view of systems biology, resulting in helpful stochastic and deterministic models and providing clearer understanding of the disease by simplification ofmalignant clonal evolution processes (Vesely et al., 2011; Amir et al., 2013; Paguirigan et al., 2015). However, models fitted to experimental data must strike a balance between simplicity and reality, so that they can bring insights into clinical scenarios. Here we discuss the importance and challenges of incorporating the BM microenvironment into AL modeling, as a key element that will control the interplay between cell populations and the selective pressure leading to leukemic or normal hematopoiesis progression. By developing integrative tools that better mimic and predict the behavior of heterogeneous and polyclonal cells in the context of abnormal microenvironments within leukemic bone marrow, we may learn about crucial mechanisms co-participating in the etiology and progression of the disease.