PPAR-γ Agonists Induce Growth Arrest of Kit/AML1-ETO Leukemia Cells Acting on Diverse Pathways

• Published in: Blood 2014-12, Vol.124 (21), p.5211-5211
• Main Authors: Agosti, Valter, Talarico, Daniela, Urzino, Agostina, Murthi, Raghavendra Vasudeva, Nocera, Aurora Anna Rita, Giovannone, Emilia Dora
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.5211.5211

Translocation 8;21, t(8;21), with an incidence of up to 12% is among the most common genetic aberrations found in Acute Myeloid leukemias (AMLs). t(8;21) rearranges the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generating an AML1-ETO fusion protein. It acts as dominant-negative repressor of genes involved in cell cycle control and myeloid differentiation. Despite its critical role in tumor initiation, AML1-ETO is not sufficient, per se, to cause an overt leukemia. It has to cooperate with other genetic alterations, such as those involving receptor tyrosine kinases. KIT tyrosine kinase gain-of-function mutations have been detected in about 50% of t(8;21) AMLs. Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) agonists are known to inhibit proliferation and induce apoptosis in cancer cells, including those from hematologic malignancies. Despite several promising pre-clinical studies, results of clinical trials are not conclusive so far. We investigated the effects and mechanisms of action of some PPAR-γ agonists in an AML1-ETO/Kit activated leukemia cell line: Kasumi-1. Troglitazone (TGZ) and rosiglitazone (RGZ) reduced proliferation rate and clonogenic potential of Kasumi-1, inducing G1 arrest and apoptosis in a dose and time dependent manner. Activated Kit induces proliferation mostly through the Src kinases/Ras/MAPK pathway. Erk1/2 is constitutively phosphorylated in Kasumi-1 cells and exposure to troglitazone (50μM) significantly reduced its phosphorylated state even if not as much as imatinib. The Kit signaling cascades include activation of PI3-kinase/AKT pathway, but surprisingly TGZ treatment did not affect AKT phosphorylation. It has been shown that PPAR agonists 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid (CDDO) and 15-Deoxy-Δ12,14-ProstaglandinJ2 (15d-PGJ2) are able to suppress TGFβ-induced phosphorylation of AktS473, leading an anti-fibrotic activity in the lung. CDDO and 15d-PGJ2 inhibition effect have been demonstrated direct, PPAR-γindependent and mostly related to electrophilic carbons present in their structures. In the same cellular context rosiglitazone was found relatively poorly effective. We compared, in Kasumi-1 cells, activity of 15d-PGJ2 and CAY10410, two PPAR agonists with similar structure but while 15d-PGJ2 has an electrophilic center CAY10410 does not. CAY10410 is a strong PPAR agonist but was unable to induce any reduction in Kasumi-1 cells proliferation rate or induce apoptosis whereas 15d-PGJ2 str