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Halofuginone Has Anti-Proliferative Effects in Acute Promyelocytic Leukemia by Modulating the Transforming Growth Factor Beta Signaling Pathway
Published: Friday, October 28, 2011
Author: Lorena L. de Figueiredo-Pontes et al.

by Lorena L. de Figueiredo-Pontes, Patricia A. Assis, Bárbara A. A. Santana-Lemos, Rafael H. Jácomo, Ana Sílvia G. Lima, Aglair B. Garcia, Carolina H. Thomé, Amélia G. Araújo, Rodrigo A. Panepucci, Marco A. Zago, Arnon Nagler, Roberto P. Falcão, Eduardo M. Rego

Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARa) expression in acute promyelocytic leukemia (APL) impairs transforming growth factor beta (TGFß) signaling, leading to cell growth advantage. Halofuginone (HF), a low-molecular-weight alkaloid that modulates TGFß signaling, was used to treat APL cell lines and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice subjected to transplantation with leukemic cells from human chorionic gonadotrophin-PML-RARa transgenic mice (TG). Cell cycle analysis using incorporated bromodeoxyuridine and 7-amino-actinomycin D showed that, in NB4 and NB4-R2 APL cell lines, HF inhibited cellular proliferation (P<0.001) and induced apoptosis (P?=?0.002) after a 24-hour incubation. Addition of TGFß revealed that NB4 cells were resistant to its growth-suppressive effects and that HF induced these effects in the presence or absence of the cytokine. Cell growth inhibition was associated with up-regulation of TGFß target genes involved in cell cycle regulation (TGFB, TGFBRI, SMAD3, p15, and p21) and down-regulation of MYC. Additionally, TGFß protein levels were decreased in leukemic TG animals and HF in vivo could restore TGFß values to normal. To test the in vivo anti-leukemic activity of HF, we transplanted NOD/SCID mice with TG leukemic cells and treated them with HF for 21 days. HF induced partial hematological remission in the peripheral blood, bone marrow, and spleen. Together, these results suggest that HF has anti-proliferative and anti-leukemic effects by reversing the TGFß blockade in APL. Since loss of the TGFß response in leukemic cells may be an important second oncogenic hit, modulation of TGFß signaling may be of therapeutic interest.
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