BBB seminar: Bjørn Tore Gjertsen
Single cell profiling of phospho-protein networks in acute myeloid leukemia – from signaling profiles to future biomarkers of therapy response
Bjørn Tore Gjertsen
Institute of Medicine, Haematology Section, Haukeland University Hospital, University of Bergen
Acute myeloid leukemia (AML) is a hematopoietic stem cell malignancy characterized by blocked differentiation, proliferation and deteriorating suppression of normal bone marrow function. The current hypothesis for leukemogenesis proposes a combination of constitutive tyrosine kinase signaling and aberrant transcriptional regulation. In Norway we have approximately 120 new cases of AML every year, predominantly in the higher age groups. Long-term survival is below 40%, which underscores the need for development of more effective and less toxic treatments.
Using multiparameter flow cytometry, we have previously shown how multiple phosphosignaling proteins can be monitored at the single AML cell level briefly after defined growth factor stimulation (Irish et al., Cell 2004, 118:217-28). By exposing AML cell signaling 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, partly through distinct modulation of apoptosis regulating mechanisms (Irish et al., Blood 2007, 109:2589-96).
Strikingly, individual AML patients manifested multiple cell subsets with unique network profiles, reflecting heterogeneity at the level of signaling response. Recent experiments propose that this signaling response heterogeneity determines cancer cell fate early during chemotherapy. Genetic alteration of the cancer cells is reflected in response to potentiated inputs, and a model for signal amplification or controlled switch in AML is presented.
We have explored non-genotoxic therapy in AML, based on combination of signal transduction modulation, transcriptional regulation and epigenetics, revealing dramatic remodeling of signaling networks in advanced and resistant AML (Anensen et al., Leukemia 2006, 20:734-6). Thus, single cell profiling of signaling networks allow both categorization of AML patients and efficiency surveillance of future therapy.
Host: Helge Wiig <helge.wiig[@]biomed.uib.no>, Dept. of Biomedicine