Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia

Śniegocka, Martyna; Liccardo, Francesca; Fazi, Francesco; Masciarelli, Silvia

doi:10.1016/j.drup.2022.100853

Cited by 19 publications

(19 citation statements)

References 167 publications

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“…The most promising strategy to restrict this phenomenon is to target different oncogenic/survival pathways in combination. Protein homeostasis is essential for cell survival and leukemia cells depend on adaptive stress responses 18,46,47 . We have already demonstrated that FLT3-ITD + AML cells are particularly sensitive to proteostasis unbalance, also because this mutated protein is unfolded and retained in the ER by its quality control systems 19 .…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest that a possible strategy is to combine multiple approaches targeting different pro-survival pathways. Leukemic cells rely on adaptive responses to cope with intrinsic and extrinsic sources of proteotoxic stresses, that result in the disruption of protein homeostasis 18 . In this context, we set up an approach based on the induction of endoplasmic reticulum (ER) and oxidative stress that showed cytotoxic activity against FLT3-ITD + AML, both in cell lines and primary blasts isolated from patients 19 .…”

Section: Introductionmentioning

confidence: 99%

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Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection

Liccardo

Śniegocka

Tito

et al. 2023

Preprint

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Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A). It exerts strong cytotoxic activity on FLT3-ITD+ AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with bone marrow stromal cells (BMSC). Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination of RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+ AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML cells and BMSC upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSC. Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+ AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML cells and BMSC, involving mechanotransduction and YAP signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection

Liccardo

Śniegocka

Tito

et al. 2023

Preprint

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“…Interestingly, we noticed that endoplasmic reticulum (ER) stress is involved in all these mechanisms [11][12][13]. ER stress regulates cellular proteostasis in response to external or internal stimuli and determines cell fate through various pro-survival or pro-death mechanisms, such as autophagy, apoptosis, and cell cycle arrest [14,15]. Studies have shown that activated ER stress can enhance the sensitivity of AML cells to chemotherapeutic drugs [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

The ER stress related gene panel guide the prognosis and chemosensitivity in acute myeloid leukemia

Ren,

Peng,

Long

et al. 2024

Preprint

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Background Acute myeloid leukemia possess high heterogeneity and current European Leukemia Net (ELN) risk stratification system cannot be applicable to all AML patients and needs about 3 weeks testing cycle. The aim of this study was to develop a applicable prognostic tool that may overcome the above shortcomings. Methods We used AML patients collected in clinic and TCGA database to explore the role of ER stress in response to chemotherapy. Patients from the TCGA database were used as the training cohort, and two GEO datasets were used as external validation cohorts. Univariate /multivariate COX and LASSO regression was exemplified to establish the prognostic model. Kaplan-Meier and time-dependent ROC were used to assess and compare the efficiency of the model with ELN stratification and other models. R package "pRRophetic" was utilized to assess drug sensitivity. Results In the training cohort, we selected 5 ER stress-related genes to predict chemosensitivity and establish the ERS-5 prognostic model. The model successfully predicted the overall survival of patients; p < 0.0001, HR = 4.86 (2.79–8.44); AUC = 0.83. The model was verified in validation cohorts and could further stratify the risk of various AML subgroups. It also complemented the ability of ELN to predict the response of patients with AML to main chemotherapeutic drugs. Finally, a “ERS-5” risk score was construced by the nomogram based on the ERS-5 model and age. Conclusions The ERS-5 model allowed more rapid (about 3 hours) and accurate risk stratification and complemented the ability of ELN to assess chemosensitivity.

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“…When these mechanisms of adaptation are not sufficient to handle proteostasis alterations, cells undergo apoptosis. Thus, there is a growing interest in targeting proteostasis to induce death of cancer cells ( Marciniak et al, 2022 ; Wolska-Washer and Smolewski, 2022 ; Śniegocka et al, 2022 ). In this context, a review article in this Research Topic discusses the potential of using ascorbic acid (Vitamin C) as an adjuvant therapy for acute myeloid leukemia on the basis of its role in epigenetics and of its pro-oxidant properties ( Travaglini et al ).…”

Section: Introductionmentioning

confidence: 99%

Editorial: Protein homeostasis in growth, development and disease

Masciarelli

Fazi²,

Hendershot³

2023

Front. Cell Dev. Biol.

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Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia

Cited by 19 publications

References 167 publications

Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection

Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection

The ER stress related gene panel guide the prognosis and chemosensitivity in acute myeloid leukemia

Editorial: Protein homeostasis in growth, development and disease

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