Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia

Guan, Yihong; Greenberg, Edward; Hasipek, Metis; Chen, Shi; Liu, Xiaochen; Kerr, Cassandra M; Gackowski, Daniel; Zarakowska, Ewelina; Radivoyevitch, Tomas; Gu, Xiaorong; Willard, Belinda; Visconte, Valeria; Makishima, Hideki; Nazha, Aziz; Mukherji, Mridul; Sekeres, Mikkael A.; Saunthararajah, Yogen; Oliński, Ryszard; Xu, Mingjiang; Maciejewski, Jaroslaw P.; Jha, Babal K.

doi:10.1038/s42003-020-01220-9

Cited by 36 publications

(31 citation statements)

References 60 publications

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“…Likewise, our group confirmed that long-term AA treatment prevented MN evolution in Tet2-deficient murine models [17]. However, TET2 loss due to catalytic domain lysine acetylation or missense mutations prevented this beneficial effect, which was restored by the additional use of class I and II histone deacetylase inhibitors [17]. Lower than normal AA levels have been found in patients with MN, and AA has been used at supraphysiological doses in a case of TET2 mutant AML, confirming its potential therapeutic role in TET2-mutant MN [48].…”

Section: Tet2 As An Actionable Targetsupporting

confidence: 67%

“…Moreover, AA was able to restore 5-hmC formation, drive DNA hypomethylation and expression of a TET2 gene signature, and ultimately suppressed leukemia progression in patient-derived xenografts (PDXs) [47]. Likewise, our group confirmed that long-term AA treatment prevented MN evolution in Tet2-deficient murine models [17]. However, TET2 loss due to catalytic domain lysine acetylation or missense mutations prevented this beneficial effect, which was restored by the additional use of class I and II histone deacetylase inhibitors [17].…”

Section: Tet2 As An Actionable Targetsupporting

confidence: 57%

“…The carboxyl (C)-terminus of all three TET family members harbors the oxygenase catalytic domain and the binding sites for 2-oxoglutarate (α-KG) and Fe 2+ , which are both critical cofactors for TET oxidative activity [16]. TET proteins progressively oxidize 5-mC to 5-hmC, 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC), creating a pool of TET-dependent 5-mC-DNA oxidation products (TDOP) which ultimately can be reverted to cytosine via thymine DNA glycosylase-mediated base excision repair [16,17]. (Figure 2) Therefore, TET proteins are critical regulators of DNA demethylation via the generation of 5-hmC, ultimately leading to enhanced gene expression and transcription profiles responsible for cell proliferation and survival [18][19][20].…”

Section: The Metabolomics Of Tet Family Of Genesmentioning

confidence: 99%

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The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

Gurnari

Pagliuca

Visconte

2021

IJMS

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The study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a window of therapeutic opportunities between normal and neoplastic cells, considering that all or most of the metabolic pathways important for cancer ontogeny may also regulate physiological cell functions. Targeted therapies have used the properties of leukemic cells to produce altered metabolic products when mutated. This is the case of IDH1/2 mutations generating the abnormal conversion of α-ketoglutarate (KG) to 2-hydroxyglutarate, an oncometabolite inhibiting KG-dependent enzymes, such as the TET family of genes (pivotal in characterizing leukemia cells either by mutations, e.g., TET2, or by altered expression, e.g., TET1/2/3). Additional observations derive from the high sensitivity of leukemic cells to oxidative phosphorylation and its amelioration using BCL-2 inhibitors (Venetoclax) or by disrupting the mitochondrial respiration. More recently, nicotinamide metabolism has been described to mediate resistance to Venetoclax in patients with acute myeloid leukemia. Herein, we will provide an overview of the latest research on the link between metabolic pathways interactome and leukemogenesis with a comprehensive analysis of the metabolic consequences of driver genetic lesions and exemplificative druggable pathways.

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Section: Tet2 As An Actionable Targetsupporting

confidence: 67%

Section: Tet2 As An Actionable Targetsupporting

confidence: 57%

Section: The Metabolomics Of Tet Family Of Genesmentioning

confidence: 99%

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The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

Gurnari

Pagliuca

Visconte

2021

IJMS

Self Cite

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“…Consistently, in acute myeloid leukemia (AML) cells with TET2 mutations, treatment with vitamin C mimicked TET2 restoration by increasing TET activity ( Figure 4 ) and blocked leukemia progression in patient-derived tumor xenograft models [ 102 ]. However, the ability of vitamin C to restore TET2 activity seems to depend on N- and C-terminal lysine acetylation and type of TET2 mutations [ 103 ].…”

Section: Mechanisms Of Vitamin C Anticancer Actionmentioning

confidence: 99%

High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients

Giansanti

Karimi

Faraoni

et al. 2021

Cancers

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High-dose vitamin C has been proposed as a potential therapeutic approach for patients with advanced tumors who failed previous treatment with chemotherapy. Due to vitamin C complex pharmacokinetics, only intravenous administration allows reaching sufficiently high plasma concentrations required for most of the antitumor effects observed in preclinical studies (>0.250 mM). Moreover, vitamin C entry into cells is tightly regulated by SVCT and GLUT transporters, and is cell type-dependent. Importantly, besides its well-recognized pro-oxidant effects, vitamin C modulates TET enzymes promoting DNA demethylation and acts as cofactor of HIF hydroxylases, whose activity is required for HIF-1α proteasomal degradation. Furthermore, at pharmacological concentrations lower than those required for its pro-oxidant activity (<1 mM), vitamin C in specific genetic contexts may alter the DNA damage response by increasing 5-hydroxymethylcytosine levels. These more recently described vitamin C mechanisms offer new treatment opportunities for tumors with specific molecular defects (e.g., HIF-1α over-expression or TET2, IDH1/2, and WT1 alterations). Moreover, vitamin C action at DNA levels may provide the rationale basis for combination therapies with PARP inhibitors and hypomethylating agents. This review outlines the pharmacokinetic and pharmacodynamic properties of vitamin C to be taken into account in designing clinical studies that evaluate its potential use as anticancer agent.

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“…In particular, it has been shown that interleukin-1β upregulates the expression of P-selectin in endothelial cells, a known chemo-attracting agent for monocytes, currently evaluated as a possible actionable target in the setting of CHIP and MDS to decrease cardiovascular risk [ 68 , 69 ]. Another approach currently in evaluation is the use of vitamin C, taking into account the recent data on its role in restoring some TET2 functions [ 70 , 71 ]. However, as discussed, a growing body of evidence regarding the underlying link between CHIP and increased cardiovascular risk points towards the presence of deregulated inflammation, providing favorable conditions for the CHIP clone(s) to expand and produce hyper-inflammatory leukocytes/monocytes, ultimately leading to cardiovascular events [ 72 ].…”

Section: Clinical Implications Of Chip: a Focus On Cardiovascular mentioning

confidence: 99%

From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms: The Silent Way of Cancer Progression

Gurnari

Fabiani

Falconi

et al. 2021

Biology

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Clonal hematopoiesis (CH) has been recognized as a predisposing factor for the development of myeloid malignancies. Its detection has been reported at different frequencies across studies, based on the type of genome scanning approach used and the population studied, but the latest insights recognize its virtual ubiquitous presence in older individuals. The discovery of CH in recent years paved the way for a shift in the paradigm of our understanding of the biology of therapy-related myeloid malignancies (t-MNs). Indeed, we moved from the concept of a treatment-induced lesion to a model where CH precedes the commencement of any cancer-related treatment in patients who subsequently develop a t-MN. Invariant patterns of genes seem to contribute to the arising of t-MN cases, with differences regarding the type of treatment received. Here, we review the principal studies concerning CH, the relationship with myeloid progression and the mechanisms of secondary t-MN development.

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Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia

Cited by 36 publications

References 60 publications

The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients

From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms: The Silent Way of Cancer Progression

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