Abstract
AbstractAcute myeloid leukemia (AML) is an aggressive malignancy with a relapse rate approaching 50%, despite aggressive chemotherapy. New therapies for AML are targeted at signal transduction pathways known to support blast survival, such as the Stat3 pathway. Aberrant activation of Stat3 has been demonstrated in many different malignancies, including AML, and this finding is frequently associated with more aggressive disease. The objectives of this study were: (1) to characterize Stat3 signaling patterns in AML cells lines and primary pediatric samples; and (2) to test the efficacy and potency of a novel Stat3 inhibitor in inducing apoptosis in AML cells. We found that Stat3 was constitutively activated in 6 of 7 AML cell lines and 6 of 18 primary pediatric AML samples. Moreover, constitutively phosphorylated Stat3 was frequent in samples with normal karyotype but uncommon in samples with t(8;21). Most cell lines and primary samples responded to G-CSF stimulation, although the sensitivity and magnitude of the response varied dramatically. Our novel small-molecule Stat3 inhibitor, C188-9, inhibited G-CSF–induced Stat3 phosphorylation, induced apoptosis in AML cell lines and primary samples, and inhibited AML blast colony formation with potencies in the low micromolar range. Therefore, Stat3 inhibition may be a valuable strategy for targeted therapies for AML.
Highlights
Stat[3] is a critical signaling intermediate in hematopoietic cells that is activated by recruitment to tyrosine-phosphorylated receptor complexes, including the granulocyte colony-stimulating factor (G-CSF) receptor
Constitutively active Stat[3] was first demonstrated in squamous cell carcinoma of the head and neck[5] and since has been demonstrated in many different cancers, including acute myeloid leukemia (AML),[6,7,8] notably no studies have been done with pediatric patients
We report the prevalence of constitutive and G-CSF–induced tyrosine-phosphorylated Stat[3] in a panel of AML cell lines and a cohort of primary pediatric AML samples, and the effects of Stat[3] inhibition on AML cell growth and survival
Summary
Stat[3] is a critical signaling intermediate in hematopoietic cells that is activated by recruitment to tyrosine-phosphorylated receptor complexes, including the granulocyte colony-stimulating factor (G-CSF) receptor. Recruitment leads to phosphorylation of Stat[3] on tyrosine 705 (pY705), tail-to-tail dimerization, nuclear accumulation, and gene transcription. The evidence that Stat[3] signaling plays a key role in cancer was first obtained from cells transformed by the oncogene v-src.[2] Subsequently, several other oncoproteins that activate tyrosine kinase pathways were shown to result in constitutive Stat[3] activation.[3] Fibroblasts expressing a constitutively active Stat[3] mutant (Stat3-C) developed malignant properties in culture and formed tumors in nude mice.[4] Clinically, constitutively active Stat[3] was first demonstrated in squamous cell carcinoma of the head and neck[5] and since has been demonstrated in many different cancers, including acute myeloid leukemia (AML),[6,7,8] notably no studies have been done with pediatric patients. Recent studies have demonstrated that acquired resistance to tyrosine kinase inhibitors (TKI) can be attributed in some cases to increased activity of the Stat[3] pathway, and Stat[3] inhibition restores TKI sensitivity.[9,10]
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