BBB seminar: Bjørn Tore Gjertsen
Potentiated phospho-protein networks in leukemic cells
Bjørn Tore Gjertsen
Hematology Section, Department of Internal Medicine, Haukeland University Hospital, University of Bergen
Acute myeloid leukemia (AML) is a stem cell malignancy characterised by blocked differentiation, usually followed by extensive proliferation and deteriorating suppression of normal bone marrow function. In Norway we have approximately 200 new cases of AML every year, predominantly in the higher age groups. Long-term survival is below 20%, which underscores the need for the development of more effective and less toxic treatments.
The current hypothesis for leukemogenesis suggests that the neoplasia is formed by constitutive activation of a tyrosine kinase in combination with an aberrant transcription factor. To our surprise, presence of the activating mutation of the receptor tyrosine kinase Flt3 fluctuates and is unstable during relapse of the disease. This raises several questions with respect to maintenance of the disease, and has practical implications for the follow up of patients. An alternative approach of mapping mutated receptors in leukemia may be to determine signalling network profiles of the leukemic cells.
Altered growth factor responses in phospho-protein-driven signalling networks are crucial to AML cell survival and pathology. Profiles of AML cell signalling networks might therefore identify mechanisms by which such cells interpret environmental cues for continued growth. Using multiparameter flow cytometry, we monitored phospho-protein responses to environmental cues in acute myeloid leukemia at the single cell level. By exposing AML cell signalling networks to potentiating inputs, rather than relying upon the basal levels of protein phosphorylation alone, we could discern unique cancer network profiles that correlated with genetics and disease outcome. Strikingly, individual AML patients manifested multiple cell subsets with unique network profiles, reflecting heterogeneity at the level of signalling response. The results revealed a dramatic remodelling of signalling networks in AML cells. Thus, single cell measurements of phospho-protein responses reveal shifts in signalling potential of a phospho-protein network, allowing for categorization of cell network phenotypes by multidimensional molecular profiles of signalling.
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