Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53.

Irish JM, Anensen N, Hovland R, Skavland J, Børresen-Dale AL, Bruserud O, Nolan GP, Gjertsen BT
Blood. 2007 109 (6): 2589-96

PMID: 17105820 · DOI:10.1182/blood-2006-02-004234

Loss or mutation of the TP53 tumor suppressor gene is not commonly observed in acute myeloid leukemia (AML), suggesting that there is an alternate route for cell transformation. We investigated the hypothesis that previously observed Bcl-2 family member overexpression suppresses wild-type p53 activity in AML. We demonstrate that wild-type p53 protein is expressed in primary leukemic blasts from patients with de novo AML using 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and phospho-specific flow cytometry. We found that p53 was heterogeneously expressed and phosphorylated in AML patient samples and could accumulate following DNA damage. Overexpression of antiapoptosis protein Bcl-2 in AML cells was directly correlated with p53 expression and phosphorylation on serine residues 15, 46, and 392. Within those patients with the highest levels of Bcl-2 expression, we identified a mutation in FLT3 that duplicated phosphorylation site Y591. The presence of this mutation correlated with greater than normal Bcl-2 expression and with previously observed profiles of potentiated STAT and MAPK signaling. These results support the hypothesis that Flt3-mediated signaling in AML enables accumulation of Bcl-2 and maintains a downstream block to p53 pathway apoptosis. Bcl-2 inhibition might therefore improve the efficacy of existing AML therapies by inactivating this suppression of wild-type p53 activity.

MeSH Terms (16)

Cells, Cultured DNA Damage Electrophoresis, Gel, Two-Dimensional fms-Like Tyrosine Kinase 3 Gene Expression Gene Expression Profiling Gene Expression Regulation, Leukemic Humans Leukemia, Myeloid, Acute Mutation Phosphorylation Protein Isoforms Proto-Oncogene Proteins c-bcl-2 Signal Transduction Tumor Suppressor Protein p53 Tyrosine

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