scholarly journals Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia

Leukemia ◽  
2014 ◽  
Vol 28 (12) ◽  
pp. 2324-2335 ◽  
Author(s):  
V Kumar ◽  
R Palermo ◽  
C Talora ◽  
A F Campese ◽  
S Checquolo ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathways ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5′AMP-Activated Kinase Inactivation

2021 ◽  
Vol 22 (12) ◽  
pp. 6384
Author(s):  
Valeria Tosello ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
Cinzia Franchin ◽  
Paola Zanovello ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathways ◽  
Lymphoblastic Leukemia ◽  
Metabolic Adaptation ◽  
Serum Starvation ◽  
Ampk Signaling ◽  
Compound C ◽  
Gli1 Expression ◽  
Cell Acute Lymphoblastic Leukemia

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.

Targeting Signaling Pathways in T-cell acute lymphoblastic leukemia initiating cells

2014 ◽  
Vol 56 ◽  
pp. 6-21 ◽  
Author(s):  
Alberto M. Martelli ◽  
Annalisa Lonetti ◽  
Francesca Buontempo ◽  
Francesca Ricci ◽  
Pier Luigi Tazzari ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathways ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

New advances in targeting aberrant signaling pathways in T-cell acute lymphoblastic leukemia

2019 ◽  
Vol 74 ◽  
pp. 100649 ◽  
Author(s):  
Francesca Paganelli ◽  
Annalisa Lonetti ◽  
Laura Anselmi ◽  
Alberto M. Martelli ◽  
Camilla Evangelisti ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathways ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia
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