Scientists have traditionally studied complex biologic systems by reducing them to simple building blocks. Genome sequencing, high-throughput screening, and proteomics have, however, generated large datasets, revealing a high level of complexity in components and interactions. Systems biology embraces this complexity with a combination of mathematical, engineering, and computational tools for constructing and validating models of biologic phenomena. The validity of mathematical modeling in hematopoiesis was established early by the pioneering work of Till and McCulloch. In reviewing more recent papers, we highlight deterministic, stochastic, statistical, and network-based models that have been used to better understand a range of topics in hematopoiesis, including blood cell production, the periodicity of cyclical neutropenia, stem cell production in response to cytokine administration, and the emergence of imatinib resistance in chronic myeloid leukemia. Future advances require technologic improvements in computing power, imaging, and proteomics as well as greater collaboration between experimentalists and modelers. Altogether, systems biology will improve our understanding of normal and abnormal hematopoiesis, better define stem cells and their daughter cells, and potentially lead to more effective therapies. (Blood. 2010;115:2339-2347) IntroductionDespite advances made in identifying genes, epigenetic modifiers, lipids, proteins, and their posttranslational processing, much remains unknown about the precise roles these components play in health and disease. That biologic processes are complex and dynamic has been clearly established, albeit underappreciated. 1 One obstacle to a more complete understanding is that reductionism dominates biologists' thinking. Reductionism states that a problem can be solved by decomposing it into building blocks and studying them one at a time. 2 Large datasets of genes, lipids, metabolites, and proteins have made it impossible for one to intuit, reinforcing the appeal of reductionism. Yet, by breaking down a system one may lose properties that emerge only by virtue of the system's complexity. Systems biology approaches embrace this complexity, using engineering principles and computational methods to build and validate models using experimental data (Table 1). 3 Using these and other approaches, systems biology seeks to explain and predict the complex properties underlying normal and abnormal physiology.Biologic systems are multiscalar, functioning at the molecular, cellular, tissue, and organismismal levels. To perform their specialized functions, highly differentiated blood cells are continuously produced by stem cells. A combination of more than a dozen growth and stromal factors drive cells to divide asymmetrically, undergo differentiation, and carry out their end-cell functions. More than 10 000 genes are expressed in a B-cell lymphocyte. 4 A simple erythrocyte, enucleated and without mitochondria, contains more than 750 proteins, ignoring posttranslational modifications...

The myelodysplastic syndromes (MDSs) comprise a group of disorders characterized by multistage progression from cytopenias to acute myeloid leukemia (AML). They display exaggerated apoptosis in early stages, but lose this behavior during evolution to AML. The molecular basis for loss of apoptosis is unknown. To investigate this critical event, we analyzed phosphatidylinositol (PI) 3 0 kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3 0 kinase activates Akt through its production of 3 0 phosphoinositides. In turn, the phosphoinositides are dephosphorylated by two lipid phosphatases, PTEN and SHIP-1, in myeloid cells. We studied primary MDS-enriched bone marrow cells and bone marrow sections by western blotting, immunohistochemistry, immunocytochemistry and quantitative PCR for components of the SHIP/PTEN/PI 3 0 kinase signaling circuit. We reported constitutively activated Akt, variable levels of PTEN and uniformly decreased SHIP-1 expression in MDS progenitor cells. Overexpression of SHIP-1, but not the phosphatase-deficient form, inhibited myeloid leukemic growth. Levels of microRNA (miR)-210 and miR-155 transcripts, which target SHIP-1, were increased in CD34 þ MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3 0 untranslated region of SHIP-1 was confirmed by luciferase reporter assay. Transfection of a myeloid cell line with miR-210 resulted in loss of SHIP-1 protein expression. These data suggest that miR-155 and miR-210/SHIP-1/Akt pathways could serve as clinical biomarkers for disease progression, and that miR-155 and miR-210 might serve as novel therapeutic targets in MDS.

Src activation involves the coordinated regulation of positive and negative tyrosine phosphorylation sites. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. Here, we demonstrate that granulocyte colony-stimulating factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells, through Gab2-mediated recruitment of Shp2. After G-CSF stimulation, Lyn dynamically associates with Gab2 in a spatiotemporal manner. The dephosphorylation of phospho-Lyn Tyr507 was abrogated in Shp2-deficient cells transfected with the G-CSF receptor but intact in cells expressing phosphatase-defective Shp2. Auto-phosphorylation of Lyn Tyr396 was impaired in cells treated with Gab2 siRNA. The constitutively activated Shp2E76A directed the dephosphorylation of phospho-Lyn Tyr507 in vitro. Tyr507 did not undergo dephosphorylation in G-CSF–stimulated cells expressing a mutant Gab2 unable to bind Shp2. We propose that Gab2 forms a complex with Lyn and after G-CSF stimulation, Gab2 recruits Shp2, which dephosphorylates phospho-Lyn Tyr507, leading to Lyn activation.