Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

• Published in: The Journal of experimental medicine Vol. 203; no. 2; pp. 371 - 381
• Main Authors: Radomska, Hanna S, Bassères, Daniela S, Zheng, Rui, Zhang, Pu, Dayaram, Tajhal, Yamamoto, Yukiya, Sternberg, David W, Lokker, Nathalie, Giese, Neill A, Bohlander, Stefan K, Schnittger, Susanne, Delmotte, Marie-Hélène, Davis, Roger J, Small, Donald, Hiddemann, Wolfgang, Gilliland, D Gary, Tenen, Daniel G
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 20.02.2006
• Subjects: Aged; CCAAT-Enhancer-Binding Protein-alpha - antagonists & inhibitors; CCAAT-Enhancer-Binding Protein-alpha - metabolism; CCAAT-Enhancer-Binding Protein-alpha - physiology; Cell Differentiation - drug effects; Cell Line; Enzyme Activation - genetics; Female; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Granulocytes - pathology; Humans; K562 Cells; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Male; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - metabolism; Myeloid Cells - pathology; Phosphorylation; Piperazines - pharmacology; Point Mutation; Quinazolines - pharmacology; Serine - metabolism; Tumor Cells, Cultured; U937 Cells
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20052242

Mutations constitutively activating FLT3 kinase are detected in approximately 30% of acute myelogenous leukemia (AML) patients and affect downstream pathways such as extracellular signal-regulated kinase (ERK)1/2. We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein alpha (C/EBPalpha) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts. In MV4;11 cells, pharmacological inhibition of either FLT3 or MEK1 leads to granulocytic differentiation. Differentiation of MV4;11 cells was also observed when C/EBPalpha mutated at serine 21 to alanine (S21A) was stably expressed. In contrast, there was no effect when serine 21 was mutated to aspartate (S21D), which mimics phosphorylation of C/EBPalpha. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPalpha may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.