Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce cell death in FLT3-ITD+ AML

Masciarelli, Silvia; Capuano, Ernestina; Ottone, Tiziana; Divona, Mariadomenica; Lavorgna, Serena; Liccardo, Francesca; Śniegocka, Martyna; Travaglini, Serena; Noguera, Nélida I.; Picardi, Alessandra; Petrozza, Vincenzo; Fatica, Alessandro; Tamagnone, Luca; Voso, Maria Teresa; Coco, Francesco Lo; Fazi, Francesco

doi:10.1182/bloodadvances.2019000540

Cited by 24 publications

(26 citation statements)

References 21 publications

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“…A very recent article has demonstrated that a combined treatment consisting of low concentrations of retinoic acid (RA), of the ER stressor tunicamycin, and of arsenic trioxide (ATO), led to ER and oxidative stresses as well as to UPR in AML cells expressing fusion proteins such as MLL-AF4, MLL-AF6, MLL-AF9, or FLT3-internal tandem duplication (ITD), alone or in combination. The treatment caused an accumulation of mutant FLT3 protein in the ER and decreased the colony-forming capacity of primary leukemic cells bearing the FLT3-ITD mutation without affecting healthy human HPCs isolated from the BM [127]. It is worth highlighting here that the FLT3-ITD fusion protein is detected in~25-30% of AML cases and is a misfolded protein mostly retained in the ER.…”

Section: Therapeutic Strategies For Amlmentioning

confidence: 83%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

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Section: Therapeutic Strategies For Amlmentioning

confidence: 83%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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“…Experiments with cell lines, xenografts, and primary AML samples indicated that inhibition of the SUMO pathway may sensitize AML cells to atRA [97]. Similarly, the endoplasmatic reticulum-stress inducing drug tunicamycin was reported to cooperate with atRA and ATO to inhibit the clonogenic capacity and to promote death of human AML cell lines and primary AML cells, particularly those with a FLT3-ITD [98]. Another set of in vitro experiments led to the suggestion that inhibition of the histone acetyltransferase GCN5 and/or the lysine demethylase LSD1 augmented the antileukemic activities of atRA [99].…”

Section: Atra In Non-apl Aml: Preclinical Studiesmentioning

confidence: 99%

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive, often fatal hematopoietic malignancy. All-trans retinoic acid (atRA), one of the first molecularly targeted drugs in oncology, has greatly improved the outcome of a subtype of AML, acute promyelocytic leukemia (APL). In contrast, atRA has so far provided little therapeutic benefit in the much larger group of patients with non-APL AML. Attempts to identify genetically or molecularly defined subgroups of patients that may respond to atRA have not yielded consistent results. Since AML is a stem cell-driven disease, understanding the effectiveness of atRA may require an appreciation of its impact on AML stem cells. Recent studies reported that atRA decreased stemness of AML with an FLT3-ITD mutation, yet increased it in AML1-ETO driven or EVI1-overexpressing AML. This review summarizes the role of atRA in normal hematopoiesis and in AML, focusing on its impact on AML stem cells.

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“…A number of studies have implicated that ER stress is of vital importance in the treatment of AML. For example, the combination of ER stress activator tunicamycin with conventional anti-AML drugs, such as arsenic trioxide and retinoic acid, has been found to induce cell apoptosis significantly [18,19]. A previous study has observed that GSK-J4 can promote the differentiation of neuroblastoma cells via ER stress [20], indicating that ER stress plays a potential role in GSK-J4 treatment.…”

mentioning

confidence: 99%

GSK-J4 induces cell cycle arrest and apoptosis via ER stress and the synergism between GSK-J4 and decitabine in acute myeloid leukemia KG-1a cells

Chu

Liu

et al. 2020

Cancer Cell Int

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Background: GSK-J4 is the inhibitor of H3K27me3 demethylase. Recent studies demonstrated that GSK-J4 could affect the proliferation and apoptosis of a variety of cancer cells. However, the effects and underlying mechanisms of GSK-J4 on the proliferation and apoptosis of human acute myeloid leukemia (AML) KG-1a cells have not been explored thoroughly. Methods: The effect of GSK-J4 on cell proliferation was assessed with CCK8, while cell cycle distribution and apoptosis were analyzed using flow cytometry. The proteins related to cell cycle, cell apoptosis, endoplastic reticulum (ER) stress and PKC-α/p-Bcl2 pathway were detected by Western blotting. The expression level of PKC-α mRNA was measured by quantitative real-time PCR.ER stress inhibitor 4-phenyl butyric acid (4-PBA) was used to explore the role of ER stress in GSK-J4 induced cell-cycle arrest and cell apoptosis. The combination effects of Decitabine and GSK-J4 on KG-1a cells proliferation and apoptosis were also evaluated by CCK8, flow cytometry and immunoblot analysis. Results: GSK-J4 reduced cell viability and arrested cell cycle progression at the S phase by decreasing the expression of CyclinD1 and CyclinA2 and increasing that of P21. Moreover, GSK-J4 enhanced the expression of apoptosisrelated proteins (cle-caspase-9 and bax) and inhibited PKC-a/p-Bcl2 pathway to promote cell apoptosis. In addition, ER stress-related proteins (caspase-12, GRP78 and ATF4) were increased markedly after exposure to GSK-J4. The effects of GSK-J4 on cell cycle, apoptosis and PKC-a/p-Bcl2 pathway were attenuated after treatment with ER stress inhibitor. Furthermore, decitabine could significantly inhibit the proliferation and induce the apoptosis of KG-1a cells after combined treatment with GSK-J4. Conclusion: Taken together, this study provided evidence that ER stress could regulate the process of GSK-J4-induced cell cycle arrest, cell apoptosis and PKC-α/p-bcl2 pathway inhibition and demonstrated a potential combinatory effect of decitabine and GSK-J4 on leukemic cell proliferation and apoptosis.

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Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce cell death in FLT3-ITD+ AML

Abstract: Key Points RA synergizes with the N-glycosylation inhibitor tunicamycin and ATO to induce AML cell death via generation of ER and oxidative stress.

Cited by 24 publications

References 21 publications

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

GSK-J4 induces cell cycle arrest and apoptosis via ER stress and the synergism between GSK-J4 and decitabine in acute myeloid leukemia KG-1a cells

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