Oncogenesis induced by combined Phf6 and Idh2 mutations through increased oncometabolites and impaired DNA repair

Chen, Tsung-Chih; Yao, Chi‐Yuan; Chen, Yu-Ren; Yuan, Chang‐Tsu; Lin, Chien‐Chin; Hsu, Yueh-Chwen; Chuang, Po-Han; Kao, Chein-Jun; Li, Yi-Hung; Hou, Hsin‐An; Chou, Wen‐Chien; Tien, Hwei‐Fang

doi:10.1038/s41388-022-02193-1

Cited by 3 publications

(2 citation statements)

References 56 publications

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“…AML is a hazardous, enervating and invasive disease with a poor prognosis (23,24). IDH2 and PHD finger protein 6 mutations exert synergistic effects on leukemia formation through excessive production of 2-HG and damage to DNA repair (25). The mutated IDH2 enzyme exhibits gain-of-function activity and catalyzes the conversion of α-KG to 2-HG, which is involved in the pathogenesis of AML (26,27).…”

Section: Obstructed Hematopoietic Differentiation Caused By Idh2mentioning

confidence: 99%

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review)

et al. 2022

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As the risk of harmful environmental exposure is increasing, it is important to find suitable targets for the diagnosis and treatment of the diseases caused. Isocitrate dehydrogenase 2 (IDH2) is an enzyme located in the mitochondria; it plays an important role in numerous cell processes, including maintaining redox homeostasis, participating in the tricarboxylic acid cycle and indirectly taking part in the transmission of the oxidative respiratory chain. IDH2 mutations promote progression in acute myeloid leukemia, glioma and other diseases. The present review mainly summarizes the role and mechanism of IDH2 with regard to the biological effects, such as the mitophagy and apoptosis of animal or human cells, caused by environmental pollution such as radiation, heavy metals and other environmental exposure factors. The possible mechanisms of these biological effects are described in terms of IDH2 expression, reduced nicotine adenine dinucleotide phosphate content and reactive oxygen species level, among other variables. The impact of environmental pollution on human health is increasingly attracting attention. IDH2 may therefore become useful as a potential diagnostic and therapeutic target for environmental exposure-induced diseases.

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Section: Obstructed Hematopoietic Differentiation Caused By Idh2mentioning

confidence: 99%

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review)

et al. 2022

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“…Phf6 knockout HSCs from aged mice show transcriptional profiles similar to young HSCs, and deletion of Phf6 from older mice shows a shift towards a younger HSC transcriptome, suggesting that Phf6 loss may counteract HSC aging (5). Combination of Phf6 loss with overexpression of activating mutants of Notch1 ( 18 ) or Jak3 ( 20 ), or overexpression of wild-type Tlx3 ( 17 ) has been shown to cause T-ALL acceleration, while transgenic crosses of Phf6 deletion with Idh2 mutation produce mixed myeloid-lymphoid leukemias (21). Collectively, the role of PHF6 appears to be the repression of self-renewal, both in normal HSCs as well as in T-ALL (18).…”

Section: Introductionmentioning

confidence: 99%

PHF6 suppresses self-renewal of leukemic stem cells in AML

Jalnapurkar,

Pawar,

George

et al. 2024

Preprint

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Acute myeloid leukemia is characterized by the uncontrolled proliferation of self-renewing myeloid progenitors. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its loss increases mouse HSC self-renewal without malignant transformation. We report here that Phf6 knockout increases the aggressiveness of Hoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9-driven AML and identify a population that we term the LIC-e (leukemia initiating cells enriched) population. We find that Phf6 loss has context-specific transcriptional effects, skewing the LIC-e transcriptome to a more stem-like state. We demonstrate that LIC-e accumulation in Phf6 knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Overall, our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells.

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Transgenic IDH2R172K and IDH2R140Q zebrafish models recapitulated features of human acute myeloid leukemia

et al. 2023

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Isocitrate dehydrogenase 2 (IDH2) mutations occur in more than 15% of cytogenetically normal acute myeloid leukemia (CN-AML) but comparative studies of their roles in leukemogenesis have been scarce. We generated zebrafish models of IDH2R172K and IDH2R140Q AML and reported their pathologic, functional and transcriptomic features and therapeutic responses to target therapies. Transgenic embryos co-expressing FLT3ITD and IDH2 mutations showed accentuation of myelopoiesis. As these embryos were raised to adulthood, full-blown leukemia ensued with multi-lineage dysplasia, increase in myeloblasts and marrow cellularity and splenomegaly. The leukemia cells were transplantable into primary and secondary recipients and resulted in more aggressive disease. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in T-cell development at embryonic and adult stages. Single-cell transcriptomic analysis revealed increased myeloid skewing, differentiation blockade and enrichment of leukemia-associated gene signatures in both zebrafish models. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in interferon signals at the adult stage. Leukemic phenotypes in both zebrafish could be ameliorated by quizartinib and enasidenib. In conclusion, the zebrafish models of IDH2 mutated AML recapitulated the morphologic, clinical, functional and transcriptomic characteristics of human diseases, and provided the prototype for developing zebrafish leukemia models of other genotypes that would become a platform for high throughput drug screening.

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Oncogenesis induced by combined Phf6 and Idh2 mutations through increased oncometabolites and impaired DNA repair

Cited by 3 publications

References 56 publications

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review)

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review)

PHF6 suppresses self-renewal of leukemic stem cells in AML

Transgenic IDH2R172K and IDH2R140Q zebrafish models recapitulated features of human acute myeloid leukemia

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