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- W4361951362 abstract "<div>Abstract<p><b>Purpose:</b> The Hedgehog pathway plays an important role in stem-cell biology and malignant transformation. Therefore, we investigated the expression and prognostic impact of Hedgehog pathway members in acute myeloid leukemia (AML).</p><p><b>Experimental Design:</b> Pretreatment samples from 104 newly diagnosed AML patients (AMLSG 07-04 trial) were analyzed by qPCR, and expression of Hedgehog family members was correlated with clinical outcome. Inhibition of <i>GLI</i> by GANT61 or shRNA was investigated in AML cells <i>in vitro</i> and <i>in vivo</i>.</p><p><b>Results:</b> Expression of receptors Smoothened and Patched-1 and their downstream mediators, <i>GLI1</i>, <i>GLI2</i>, and <i>GLI3</i>, was found in AML patients in contrast to Hedgehog ligands. <i>GLI2</i> expression had a significant negative influence on event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS; <i>P</i> = 0.037, 0.026, and 0.013, respectively) and was correlated with FLT3 mutational status (<i>P</i> < 0.001). Analysis of a second, independent patient cohort confirmed the negative impact of <i>GLI2</i> on EFS and OS (<i>P</i> = 0.007 and 0.003, respectively; <i>n</i> = 290). Within this cohort, <i>GLI1</i> had a negative prognostic impact (<i>P</i> < 0.001 for both EFS and OS). Although AML cells did not express Hedgehog ligands by qPCR, AML patients had significantly increased Desert Hedgehog (DHH) plasma levels compared with healthy subjects (<i>P</i> = 0.002), in whom DHH was presumably provided by bone marrow niche cells. Moreover, the <i>GLI</i> inhibitor GANT61 or knockdown of <i>GLI1/2</i> by shRNA caused antileukemic effects, including induction of apoptosis, reduced proliferation, and colony formation in AML cells, and a survival benefit in mice.</p><p><b>Conclusions:</b> <i>GLI</i> expression is a negative prognostic factor and might represent a novel druggable target in AML. <i>Clin Cancer Res; 21(10); 2388–98. ©2015 AACR</i>.</p></div>" @default.
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- W4361951362 date "2023-03-31" @default.
- W4361951362 modified "2023-09-26" @default.
- W4361951362 title "Data from Expression of Hedgehog Pathway Mediator <i>GLI</i> Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects" @default.
- W4361951362 doi "https://doi.org/10.1158/1078-0432.c.6523305.v1" @default.
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