Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers

Yusuf, Rushdia Z.; Sáez, Borja; Sharda, Azeem; Gastel, Nick van; Yu, Vionnie W.C.; Baryawno, Ninib; Scadden, Elizabeth W; Acharya, Sanket S.; Chattophadhyay, Shrikanta; Huang, Cherrie; Viswanathan, Vasanthi S.; S'Aulis, Dana; Cobert, Julien; Sykes, David B.; Keibler, Mark A.; Das, Sudeshna; Hutchinson, John N.; Churchill, Michael; Mukherjee, Siddhartha; Lee, Dongjun; Mercier, François; Doench, John G.; Bullinger, Lars; Logan, David J.; Schreiber, Stuart L.; Stephanopoulos, Gregory; Rizzo, William B.; Scadden, David T.

doi:10.1182/blood.2019001808

Cited by 85 publications

(63 citation statements)

References 39 publications

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“…One report demonstrates that the ALDH3A2 isoform is crucial for AML survival, as it protects cells from oxidative damage and consequent cell death. Additionally, ALDH3A2 inhibition is synthetically lethal when combined with inhibition of glutathione peroxidase-4, a known inducer of ferroptosis [ 39 ]. Although some effort has been made to identify the role of specific aldehyde dehydrogenases in promoting AML growth and therapy resistance, the molecular mechanism underlying this finding remains unexplored.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

Yuan

Dana

et al. 2020

PLoS ONE

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The bone marrow microenvironment (BME) in acute myeloid leukemia (AML) consists of various cell types that support the growth of AML cells and protect them from chemotherapy. Mesenchymal stromal cells (MSCs) in the BME have been shown to contribute immensely to leukemogenesis and chemotherapy resistance in AML cells. However, the mechanism of stroma-induced chemotherapy resistance is not known. Here, we hypothesized that stromal cells promote a stem-like phenotype in AML cells, thereby inducing tumorigenecity and therapy resistance. To test our hypothesis, we co-cultured AML cell lines and patient samples with BM-derived MSCs and determined aldehyde dehydrogenase (ALDH) activity and performed gene expression profiling by RNA sequencing. We found that the percentage of ALDH+ cells increased dramatically when AML cells were co-cultured with MSCs. However, among the 19 ALDH isoforms, ALDH2 and ALDH1L2 were the only two that were significantly upregulated in AML cells co-cultured with stromal cells compared to cells cultured alone. Mechanistic studies revealed that the transforming growth factor-β1 (TGF-β1)-regulated gene signature is activated in AML cells co-cultured with MSCs. Knockdown of TGF-β1 in BM-MSCs inhibited stroma-induced ALDH activity and ALDH2 expression in AML cells, whereas treatment with recombinant TGF-β1 induced the ALDH+ phenotype in AML cells. We also found that TGF-β1-induced ALDH2 expression in AML cells is mediated by the non-canonical pathway through the activation of p38. Interestingly, inhibition of ALDH2 with diadzin and CVT-10216 significantly inhibited MSC-induced ALDH activity in AML cells and sensitized them to chemotherapy, even in the presence of MSCs. Collectively, BM stroma induces ALDH2 activity in AML cells through the non-canonical TGF-β pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

Yuan

Dana

et al. 2020

PLoS ONE

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“…Instead, p53 in colorectal cancer specifically communicates with DPP4 that interacts with NADPH oxidase 1 (NOX1), which was shown to contribute to the source of ROS in erastin-treated cells [ 26 ]. In addition, aldehyde dehydrogenase 3 family member A2 (ALDH3A2), an enzyme that oxidizes long-chain aldehydes to prevent oxidative damage, is critical to prevent ferroptosis in leukemia cells but not normal hematopoietic cells [ 103 ]. ALDH3A2 depletion leads to altered lipid composition and inability to downregulate lipid ROS which causes ALDH3A2 depletion to be synergistic with GPX4 inhibition.…”

Section: Lipid Metabolismmentioning

confidence: 99%

Metabolic Regulation of Ferroptosis in Cancer

Kim

Yun

Kim

2021

Biology

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Ferroptosis is a unique cell death mechanism that is executed by the excessive accumulation of lipid peroxidation in cells. The relevance of ferroptosis in multiple human diseases such as neurodegeneration, organ damage, and cancer is becoming increasingly evident. As ferroptosis is deeply intertwined with metabolic pathways such as iron, cyst(e)ine, glutathione, and lipid metabolism, a better understanding of how ferroptosis is regulated by these pathways will enable the precise utilization or prevention of ferroptosis for therapeutic uses. In this review, we present an update of the mechanisms underlying diverse metabolic pathways that can regulate ferroptosis in cancer.

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“…This form of regulated cell death is morphologically, biochemically and genetically distinct from other forms of cell death (e.g., apoptosis, pyroptosis, necroptosis and autophagy) and is triggered by iron-dependent accumulation of lipid peroxides [ 154 , 155 ]. While ferroptosis induction is associated with antileukemic activity in AML cell lines [ 43 , 156 , 157 ], data on MDS are currently limited. According to one recently published study, the cytosine analog used for MDS treatment, decitabine, exerts its antileukemic effect via the generation of ROS.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

EnvIRONmental Aspects in Myelodysplastic Syndrome

Petzer

Theurl

Weiss

et al. 2021

IJMS

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Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (TET2), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies.

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Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers

Cited by 85 publications

References 39 publications

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

Metabolic Regulation of Ferroptosis in Cancer

EnvIRONmental Aspects in Myelodysplastic Syndrome

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