Signaling Network Heterogeneity

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Science  06 Aug 2004:
Vol. 305, Issue 5685, pp. 755
DOI: 10.1126/science.305.5685.755b

Irish et al. set out to determine whether the variations in the genetics and clinical phenotypes of human cancer are correlated with altered responsiveness of signaling networks. They used multiparameter flow cytometry to quantify the amounts of various phosphorylated proteins in cells from 30 acute myeloid leukemia (AML) patients, normal CD33+ cells, and the HL-60 AML and U937 lymphoma cell lines. They found substantial variation among the patient samples in the basal phosphorylation states and their responsiveness to various cytokines of transcriptional regulators (STAT1, STAT3, STAT5, and STAT6), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and the stress-activated protein kinase p38. The AML patients could be classified into four groups based on basal phosphorylation status and change upon cytokine stimulation. The frequencies of cytogenetic abnormalities, Flt3 mutation (Flt3 is a receptor tyrosine kinase, and aberrant signaling through this receptor occurs in 30% of AML patients), and resistance to chemotherapy were nonrandomly distributed across the four clusters. Hence, single-cell analysis of changes in signaling network behaviors (in contrast to focusing on changes in gene expression) may make it possible to connect cancer cell heterogeneity to network-based therapies. — NG

Cell 118, 217 (2004).

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