Protein biogenesis, maturation and degradation are tightly regulated processes that are governed by a complex network of signaling pathways. The endoplasmic reticulum (ER) is responsible for biosynthesis and maturation of secretory proteins. Circumstances that alter cellular protein homeostasis, determine accumulation of misfolded and unfolded proteins in the ER, a condition defined as ER stress. In case of stress, the ER activates an adaptive response called unfolded protein response (UPR), a series of pathways of major relevance for cancer biology. The UPR plays a preeminent role in adaptation of tumor cells to the harsh conditions that they experience, due to high rates of proliferation, metabolic abnormalities and hostile environment scarce in oxygen and nutrients. Furthermore, the UPR is among the main adaptive cell stress responses contributing to the development of resistance to drugs and chemotherapy. Clinical management of Acute Myeloid Leukemia (AML) has improved significantly in the last decade, thanks to development of molecular targeted therapies. However, the emergence of treatment-resistant clones renders the rate of AML cure dismal. Moreover, different cell populations that constitute the bone marrow niche recently emerged as a main determinant leading to drug resistance. Herein we summarize the most relevant literature regarding the role played by the UPR in expansion of AML and ability to develop drug resistance and we discuss different possible modalities to overturn this adaptive response against leukemia. To this aim, we also describe the interconnection of the UPR with other cellular stress responses regulating protein homeostasis. Finally, we review the newest findings about the crosstalk between AML cells and cells of the bone marrow niche, under physiological conditions and in response to therapies, discussing in particular the importance of the niche in supporting survival of AML cells by favoring protein homeostasis.

Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia / Sniegocka, M.; Liccardo, F.; Fazi, F.; Masciarelli, S.. - In: DRUG RESISTANCE UPDATES. - ISSN 1368-7646. - 64:(2022), pp. 1-12. [10.1016/j.drup.2022.100853]

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

Sniegocka M.;Liccardo F.;Fazi F.
;
Masciarelli S.
2022

Abstract

Protein biogenesis, maturation and degradation are tightly regulated processes that are governed by a complex network of signaling pathways. The endoplasmic reticulum (ER) is responsible for biosynthesis and maturation of secretory proteins. Circumstances that alter cellular protein homeostasis, determine accumulation of misfolded and unfolded proteins in the ER, a condition defined as ER stress. In case of stress, the ER activates an adaptive response called unfolded protein response (UPR), a series of pathways of major relevance for cancer biology. The UPR plays a preeminent role in adaptation of tumor cells to the harsh conditions that they experience, due to high rates of proliferation, metabolic abnormalities and hostile environment scarce in oxygen and nutrients. Furthermore, the UPR is among the main adaptive cell stress responses contributing to the development of resistance to drugs and chemotherapy. Clinical management of Acute Myeloid Leukemia (AML) has improved significantly in the last decade, thanks to development of molecular targeted therapies. However, the emergence of treatment-resistant clones renders the rate of AML cure dismal. Moreover, different cell populations that constitute the bone marrow niche recently emerged as a main determinant leading to drug resistance. Herein we summarize the most relevant literature regarding the role played by the UPR in expansion of AML and ability to develop drug resistance and we discuss different possible modalities to overturn this adaptive response against leukemia. To this aim, we also describe the interconnection of the UPR with other cellular stress responses regulating protein homeostasis. Finally, we review the newest findings about the crosstalk between AML cells and cells of the bone marrow niche, under physiological conditions and in response to therapies, discussing in particular the importance of the niche in supporting survival of AML cells by favoring protein homeostasis.
2022
acute myeloid leukemia; bone marrow niche; ER stress; FLT3-ITD; IRS; molecular target therapy; oxidative stress; proteostasis; UPR
01 Pubblicazione su rivista::01g Articolo di rassegna (Review)
Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia / Sniegocka, M.; Liccardo, F.; Fazi, F.; Masciarelli, S.. - In: DRUG RESISTANCE UPDATES. - ISSN 1368-7646. - 64:(2022), pp. 1-12. [10.1016/j.drup.2022.100853]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1651765
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