Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells

Abstract

Objective: Signal transducers and activators of transcription (STAT) factors are critical mediators in the signal transduction of cytokine receptors. In hematopoietic and epithelial cells, activation of STAT 1 induces apoptosis and growth arrest, whereas activation of STAT3 and STAT5 transduces growth-promoting signals. We and others have previously described a high expression and constitutive activation of STAT1, 3, and 5 in AML blasts. In this report we focused on the mechanisms and also the biologic relevance of STAT activation in AML.Results.

Results: We report here that a constitutive STAT activation can be detected in up to 95% of primary AML blasts. In vitro, neither induction of the leukemic fusion protein PML-RAR alpha in U937 cells nor expression of transforming ras-mutants, but several leukemic protein tyrosine kinase (PTK), strongly induced activation of STAT3 and 5. Stable transfection of BA/F3 cells with TEL-JAK2, TEL-ABL, and BCR-ABL resulted in IL-3 independent growth and strong activation of STAT3 and STAT5 by TEL-JAK2 and TEL-ABL, but not by BCR-ABL. In addition, expression of constitutive active mutants of STAT3 and STAT5 alone were sufficient to transform BA/F3 cells.

Conclusions: These results show that STAT3 and STAT5 are activated in the majority of primary AML blasts and are major targets of leukemic fusion proteins with PTK activity. However, the STAT activation pattern by leukemic PTKs differed significantly and might reflect their transforming potential in acute (TEL-JAK2 and TEL-ABL) and chronic leukemias (p210BCR-ABL). The transforming capacity of constitutively activated STAT3 and STAT5 mutants strongly supports their fundamental role in the process of malignant transformation in hematopoietic cells.