p53 protein biosignatures in acute myeloid leukemia
Acute myelogenous leukemia in a patient with Li–Fraumeni syndrome treated with valproic acid, theophyllamine and all-trans retinoic acid: a case report. N Ånensen, J Skavland, C Stapnes, A Ryningen, A-L Børresen-Dale, B T Gjertsen and Ø Bruserud. Submitted manuscript later published in Leukemia (2006) 20, 734–736. http://dx.doi.org/10.1038/sj.leu.2404117 (708.5Kb)
Restricted access. p53 protein biosignatures correlate with chemotherapy response and survival in acute leukemia. Nina Ånensen, Werner van Belle, Øystein Bruserud and Bjørn Tore Gjertsen. Manuscript. (3.093Mb)
Correlation analysis of two-dimensional gel electrophoretic protein patterns and biological variables. Werner Van Belle, Nina Ånensen, Ingvild Haaland, Øystein Bruserud, Kjell-Arild Høgda and Bjørn Tore Gjertsen. Submitted manuscript later published in BMC Bioinformatics 2006, 7:198. http://dx.doi.org/10.1186/1471-2105-7-198 (1.356Mb)
A Distinct p53 Protein Isoform Signature Reflects the Onset of Induction Chemotherapy for Acute Myeloid Leukemia. Nina Anensen, Anne Margrete Oyan, Jean-Christophe Bourdon, Karl Henning Kalland, Oystein Bruserud and Bjorn Tore Gjertsen. Submitted manuscript, later published in Clinical Cancer Research 12(13), 3985-3992, July 1, 2006. (2.769Mb)
Restricted access. Wild type p53 is expressed and phosphorylated in leukemia cells with Flt3 Y591 amplification and Bcl-2 overexpression. Irish JM, Ånensen N, Hovland R, Børresen-Dale AL, Bruserud Ø, Nolan GP, and Gjertsen BT. Manuscript. (4.766Mb)
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p53 is a tumor suppressor protein often regarded as the guardian of the genome. It is a highly connected protein involved in many signaling processes in the cell. The inactivation of p53 through genetic mutations in TP53 is common in human cancers and can be detected in more than 50% of malignant tumors. In acute leukemia however, p53 inactivation is not normally a part of leukemogenesis and TP53 is found to be wild-type in >90% of the cases. This thesis has sought to elucidate the nature of the p53 protein regulation in acute myeloid leukemia to increase our understanding of disease development. The experiments have proposed that p53 is wild type, expressed and capable of transactivation of target genes. However, p53 phosphorylation could be correlated to expression of the anti-apoptotic protein Bcl-2 suggesting that Bcl-2 can function as a downstream block to p53-mediated apoptosis. Furthermore, Bcl-2 levels could be associated to a specific mutation in the receptor tyrosine kinase Flt3. Flt3 mutation has been found to be a strong predictor of disease relapse in AML, and driving Bcl-2 expression, thereby inhibiting the p53 pathway, may propose a new important event in leukemogenesis. This thesis has further shown that p53 exists as two main isoforms in patient material from acute myeloid leukemia. The expression of these was influenced by chemotherapy in vivo and induction of one specific form correlated to induction of known p53 target genes. The p53 protein has many known sites for post-translational modifications and serves as a substrate for many enzymes. The p53 protein may thus be a central node in a large network of proteins whose activities are critical for cell life and death. This may suggest that specific p53 signatures could serve as a ‘read-out’ for the p53 network. The expression of the described p53 isoforms were, using a novel correlation algorithm, found to be correlated to several clinical parameters including survival, remission and Flt3 mutation. This could imply that p53 may be used as a possible biomarker for clinical stratification of leukemia patients.
This doctoral thesis is based on the following articles: Paper I Wild type p53 is expressed and phosphorylated in leukemia cells with Flt3 Y591 amplification and Bcl-2 overexpression Irish JM*, Ånensen N*, Hovland R, Børresen-Dale AL, Bruserud Ø, Nolan GP, and Gjertsen BT. Manuscript. Paper II A distinct p53 protein isoform signature reflects the onset of induction chemotherapy for acute myeloid leukemia Ånensen N, Øyan AM, Abrahamsen JF, Kalland KH, Bruserud Ø, and Gjertsen BT. Manuscript submitted. Paper III Correlation analysis of two-dimensional gel electrophoretic protein patterns and biological parameters: p53 biosignatures reflect origin of cancer and stage of differentiation Van Belle W, Ånensen N, Haaland I, Bruserud Ø, and Gjertsen BT. Manuscript. Paper IV p53 protein biosignatures correlate with chemotherapy response and survival in acute leukemia Ånensen N, Van Belle W, Bruserud Ø, and Gjertsen BT. Manuscript. Paper V Acute myelogenous leukemia in a patient with Li-Fraumeni syndrome treated with valproic acid, theophyllamine and all-trans retinoic acid: A case report Ånensen N, Skavland J, Stapnes C, Ryningen A, Gjertsen BT, and Bruserud Ø. Manuscript.