The Department of Biomedicine

CCBIO Seminar: Bjørn Tore Gjertsen

Phosphoprotein signaling in acute myeloid leukemia

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Bjørn Tore Gjertsen
Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, and Department of Internal Medicine, Haukeland University Hospital

Acute myeloid leukemia (AML) is a stem cell disease of myeloid progenitor cells, characterized by blocked differentiation, anti-apoptosis and excessive proliferation. AML is biologically and clinically a heterogeneous disease, even if more than 50% of the AML patients share mutations in genes related to growth factor receptor signal transduction. In contrast to the extensive molecular characterization of AML and multiple clinical trials, substantial improvements of neither targeted nor conventional therapy have been achieved in more than 15 years.

Careful mapping of protein modulation before and after therapy in leukemic and normal blood cells has been performed to characterize and predict efficiency of response to therapy. The use of single cell analysis of intracellular signal transduction pathways depending on protein phosphorylation has provided an effective methodology to characterize both normal and cancer cells in the patient. The single cell phosphoprotein analysis may allow risk stratification at diagnosis as well as therapeutic efficiency monitoring early after start of therapy. Furthermore, multiple cancer cell clones in the patient may be detectable through this analysis of signaling responses.

Data based on carefully biobanked AML patient material indicate that analysis of basal protein phosphorylation in single AML cells provides prognostic information, surprisingly independent of the presence of the most frequent mutations in FLT3 (fms-like tyrosine kinase 3) and NPM1 (nucleophosmin 1). Results from a small clinical study illustrate how non-genotoxic therapy may benefit unfit older AML patients with chemoresistant leukemia. A strategy of individualized medicine is outlined for validation of a simplified diagnostics based on single cell phosphoprotein analysis. Careful selection of combination therapy may provide future individualized therapy transforming the acute leukemia into a more chronic disease, bearable for a better life at home. We will discuss the possibility to use a simplified phosphoprotein analysis to accurately predict an effective personalized therapy.

Selected papers:

Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368:2059-74.
••• Key paper that presents an overview of the mutational spectrum in 199 cases of AML.

Hjelle SM, Forthun RB, Haaland I, Reikvam H, Sjøholt G, Bruserud O, Gjertsen BT. Clinical proteomics of myeloid leukemia. Genome Med. 2010; 2:41.
•• Is there a role for proteomics in current diagnostics of leukemia?

Skavland J, Jørgensen KM, Hadziavdic K, Hovland R, Jonassen I, Bruserud O, Gjertsen BT. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia. Blood Cancer J. 2011; 1:e4.
• Single cell phosphoprotein screening indicates that non-genotoxic therapy benefits high risk AML patients.

Irish JM, Hovland R, Krutzik PO, Perez OD, Bruserud Ø, Gjertsen BT, Nolan GP. Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell. 2004; 118:217-28.
••• The first report that illustrates how signal response profiling of patient-derived cancer cells reflects chemoresistance and adverse mutations.

Pemovska T, Kontro M, Yadav B, et al. Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia. Cancer Discov. 2013 Nov 15. [Epub ahead of print]
••• A seminal paper that describes the combination of in vitro resistance screening and genomics to determine therapy choice in aggressive cancer.

Chair: James Lorens, CCBIO