gant-61 and Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma

gant-61 has been researched along with Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma* in 3 studies

Other Studies

3 other study(ies) available for gant-61 and Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma

ArticleYear
Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5'AMP-Activated Kinase Inactivation.
    International journal of molecular sciences, 2021, Jun-15, Volume: 22, Issue:12

    Numerous studies have shown that hedgehog inhibitors (iHHs) only partially block the growth of tumor cells, especially in vivo. Leukemia often expands in a nutrient-depleted environment (bone marrow and thymus). In order to identify putative signaling pathways implicated in the adaptive response to metabolically adverse conditions, we executed quantitative phospho-proteomics in T-cell acute lymphoblastic leukemia (T-ALL) cells subjected to nutrient-depleted conditions (serum starvation). We found important modulations of peptides phosphorylated by critical signaling pathways including casein kinase, mammalian target of rapamycin, and 5'AMP-activated kinase (AMPK). Surprisingly, in T-ALL cells, AMPK signaling was the most consistently downregulated pathway under serum-depleted conditions, and this coincided with increased GLI1 expression and sensitivity to iHHs, especially the GLI1/2 inhibitor GANT-61. Increased sensitivity to GANT-61 was also found following genetic inactivation of the catalytic subunit of AMPK (AMPKα1) or pharmacological inhibition of AMPK by Compound C. Additionally, patient-derived xenografts showing high GLI1 expression lacked activated AMPK, suggesting an important role for this signaling pathway in regulating GLI1 protein levels. Further, joint targeting of HH and AMPK signaling pathways in T-ALL cells by GANT-61 and Compound C significantly increased the therapeutic response. Our results suggest that metabolic adaptation that occurs under nutrient starvation in T-ALL cells increases responsiveness to HH pathway inhibitors through an AMPK-dependent mechanism and that joint therapeutic targeting of AMPK signaling and HH signaling could represent a valid therapeutic strategy in rapidly expanding tumors where nutrient availability becomes limiting.

    Topics: AMP-Activated Protein Kinases; Cell Death; Culture Media, Serum-Free; Enzyme Activation; Hedgehog Proteins; Humans; Jurkat Cells; Mechanistic Target of Rapamycin Complex 1; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Pyridines; Pyrimidines; Signal Transduction; Zinc Finger Protein GLI1

2021
Crosstalk between Hedgehog pathway and the glucocorticoid receptor pathway as a basis for combination therapy in T-cell acute lymphoblastic leukemia.
    Oncogene, 2020, Volume: 39, Issue:42

    Notwithstanding intensified therapy, a considerable fraction of T-cell acute lymphoblastic leukemia (T-ALL) patients face a dismal prognosis due to primary resistance to treatment and relapse, raising the need for more efficient and targeted therapies. Hedgehog (HH) signaling is a major developmental pathway frequently deregulated in cancer, for which a role in T-ALL is emerging. Mounting evidence suggests that ligand-independent activation of HH pathway occurs in cancer including T-ALL, emphasizing the necessity of dissecting the complex interplay between HH and other signaling pathways regulating activation. In this work, we present a therapeutically relevant crosstalk between HH signaling and the glucocorticoid receptor (NR3C1) pathway acting at the level of GLI1 transcription factor. GLI inhibitor GANT61 and dexamethasone were shown to exert a synergistic anti-leukemic effect in vitro in T-ALL cell lines and patient-derived xenografts. Mechanistically, dexamethasone-activated NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase and HDAC1 deacetylase. Increased GLI1 acetylation was associated with compromised transcriptional activity and reduced protein stability. In summary, our study identifies a novel crosstalk between GLI1 and NR3C1 signaling pathway which could be exploited in HH-dependent malignancies to increase therapeutic efficacy.

    Topics: Acetylation; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dexamethasone; Drug Synergism; Gene Expression Regulation, Leukemic; Hedgehog Proteins; Histone Deacetylase 1; Humans; Mice; p300-CBP Transcription Factors; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Protein Stability; Pyridines; Pyrimidines; Receptors, Glucocorticoid; Signal Transduction; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1

2020
Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors.
    Blood, 2016, 12-08, Volume: 128, Issue:23

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive childhood leukemia that is caused by the accumulation of multiple genomic lesions resulting in transcriptional deregulation and increased cell proliferation and survival. Through analysis of gene expression data, we provide evidence that the hedgehog pathway is activated in 20% of T-ALL samples. Hedgehog pathway activation is associated with ectopic expression of the hedgehog ligands Sonic hedgehog (SHH) or Indian hedgehog (IHH), and with upregulation of the transcription factor GLI1 Ectopic expression of SHH or IHH in mouse T cells in vivo caused hedgehog pathway activation in both lymphoid and epithelial cells in the thymus and resulted in increased expression of important T-cell stimulatory ligands (Dll4, Il7, and Vegf) by thymic epithelial cells. In T-ALL cell lines, pharmacological inhibition or short interfering RNA-mediated knockdown of SMO or GLI1 led to decreased cell proliferation. Moreover, primary T-ALL cases with high GLI1 messenger RNA levels, but not those with low or undetectable GLI1 expression, were sensitive to hedgehog pathway inhibition by GANT61 or GDC-0449 (vismodegib) using ex vivo cultures and in vivo xenograft models. We identify the hedgehog pathway as a novel therapeutic target in T-ALL and demonstrate that hedgehog inhibitors approved by the US Food and Drug Administration could be used for the treatment of this rare leukemia.

    Topics: Anilides; Animals; Female; Gene Expression Regulation, Leukemic; Hedgehog Proteins; Humans; Male; Mice; Neoplasm Proteins; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Pyridines; Pyrimidines; Signal Transduction; Smoothened Receptor; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1

2016