Diminished interaction between mutant NOTCH1 and the NuRD corepressor complex upregulates CCL17 in chronic lymphocytic leukemia

“…This is in concordance with known mutations in the NOTCH1 PEST domain in the ALL-SIL and DND-41 cell lines 31 which generate premature STOP codons and result in truncated NICD with longer half-life than WT 32 . Previous studies speculate that cells with NICD with longer half-life are dependent on the persistently active NOTCH1 signaling 33 . Based on this information, we wanted to know whether NOTCH1 inhibition in the PTEN- positive T-ALL cell lines with truncated NICD influences sensitivity of these cells to ASNase.…”

Section: Resultsmentioning

confidence: 98%

PTEN/PI3K/Akt pathway alters sensitivity of T-cell acute lymphoblastic leukemia to l-asparaginase

Hložková

Heřmanová

Safrhansova

et al. 2022

Sci Rep

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Childhood T-cell acute lymphoblastic leukemia (T-ALL) still remains a therapeutic challenge due to relapses which are resistant to further treatment. l-asparaginase (ASNase) is a key therapy component in pediatric T-ALL and lower sensitivity of leukemia cells to this drug negatively influences overall treatment efficacy and outcome. PTEN protein deletion and/or activation of the PI3K/Akt signaling pathway leading to altered cell growth and metabolism are emerging as a common feature in T-ALL. We herein investigated the relationship amongst PTEN deletion, ASNase sensitivity and glucose metabolism in T-ALL cells. First, we found significant differences in the sensitivity to ASNase amongst T-ALL cell lines. While cell lines more sensitive to ASNase were PTEN wild type (WT) and had no detectable level of phosphorylated Akt (P-Akt), cell lines less sensitive to ASNase were PTEN-null with high P-Akt levels. Pharmacological inhibition of Akt in the PTEN-null cells rendered them more sensitive to ASNase and lowered their glycolytic function which then resembled PTEN WT cells. In primary T-ALL cells, although P-Akt level was not dependent exclusively on PTEN expression, their sensitivity to ASNase could also be increased by pharmacological inhibition of Akt. In summary, we highlight a promising therapeutic option for T-ALL patients with aberrant PTEN/PI3K/Akt signaling.

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“…The leukemia xenografted mouse model is essential for leukemia research [1,3,6,36]. Therefore, it is particularly critical for studying the tumorigenic ability of leukemia cells and improving transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Transplantation of in vitro-manipulated cells is a widely used and powerful procedure in basic research and translational studies in the field of hematology. For example, cell line-derived xenograft mouse models are essential in studying the pathogenesis of diseases, testing the efficacy of treatment, and investigating molecular mechanisms of therapeutic resistance [1][2][3]. Ex vivo human hematopoietic stem cell (HSC) expansion and generating HSCs through in vitro reprogramming constitute a new hope for solving the issue of HSC shortage [4,5].…”

mentioning

confidence: 99%

mTORC1‐mediated amino acid signaling is critical for cell fate determination under transplant‐induced stress

Cheng

Zhu

et al. 2020

FEBS Letters

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Transplantation of in vitro-manipulated cells is widely used in hematology. While transplantation is well recognized to impose severe stress on transplanted cells, the nature of transplant-induced stress remains elusive. Here, we propose that the lack of amino acids in serum is the major cause of transplant-induced stress. Mechanistically, amino acid deficiency decreases protein synthesis and nutrient consummation. However, in cells with overactive AKT and ERK, mTORC1 is not inhibited and protein synthesis remains relatively high. This impaired signaling causes nutrient depletion, cell cycle block, and eventually autophagy and cell death, which can be inhibited by cycloheximide or mTORC1 inhibitors. Thus, mTORC1-mediated amino acid signaling is critical in cell fate determination under transplant-induced stress, and protein synthesis inhibition can improve transplantation efficiency.

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Diminished interaction between mutant NOTCH1 and the NuRD corepressor complex upregulates CCL17 in chronic lymphocytic leukemia

Cited by 7 publications

References 15 publications

Deubiquitinating enzyme inhibitor alleviates cyclin A1‐mediated proteasome inhibitor tolerance in mixed‐lineage leukemia

Deubiquitinating enzyme inhibitor alleviates cyclin A1‐mediated proteasome inhibitor tolerance in mixed‐lineage leukemia

PTEN/PI3K/Akt pathway alters sensitivity of T-cell acute lymphoblastic leukemia to l-asparaginase

mTORC1‐mediated amino acid signaling is critical for cell fate determination under transplant‐induced stress

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