The
let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins
Lin28a/
b promote malignancy by inhibiting
let-7 biogenesis. We have uncovered ...unexpected roles for the
Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both
Lin28a and
LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of
Lin28a or overexpression of
let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the
let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including
IGF1R, INSR, and
IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates
Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover,
let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the
Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.
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Lin28a/b promote glucose tolerance and insulin-sensitivity in mice ► Overexpression of
let-7 microRNA impairs glucose tolerance in mice ►
Lin28a/b promote and the
let-7's repress components of insulin-PI3K-mTOR signaling ►
Let-7 targets are enriched for type II diabetes-associated SNPs in human GWAS
The microRNA,
let-7, represses mTOR pathway components, contributing to the diabetic phenotypes of insulin resistance and impaired glucose tolerance in mice and humans.
Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism
. Mitochondria, as the major site of oxidative reactions, must maintain ...sufficient levels of GSH to perform protective and biosynthetic functions
. GSH is synthesized exclusively in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remains unknown. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, as a regulator of GSH transport into mitochondria. Loss of SLC25A39 reduces mitochondrial GSH import and abundance without affecting cellular GSH levels. Cells lacking both SLC25A39 and its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron-sulfur clusters. We find that mitochondrial GSH import is necessary for cell proliferation in vitro and red blood cell development in mice. Heterologous expression of an engineered bifunctional bacterial GSH biosynthetic enzyme (GshF) in mitochondria enables mitochondrial GSH production and ameliorates the metabolic and proliferative defects caused by its depletion. Finally, GSH availability negatively regulates SLC25A39 protein abundance, coupling redox homeostasis to mitochondrial GSH import in mammalian cells. Our work identifies SLC25A39 as an essential and regulated component of the mitochondrial GSH-import machinery.
Oligomeric assemblies of tau and the RNA-binding proteins (RBPs) Musashi (MSI) are reported in Alzheimer's disease (AD). However, the role of MSI and tau interaction in their aggregation process and ...its effects are nor clearly known in neurodegenerative diseases. Here, we investigated the expression and cellular localization of MSI1 and MSI2 in the brains tissues of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as in the wild-type mice and tau knock-out and P301L tau mouse models. We observed that formation of pathologically relevant protein inclusions was driven by the aberrant interactions between MSI and tau in the nuclei associated with age-dependent extracellular depositions of tau/MSI complexes. Furthermore, tau and MSI interactions induced impairment of nuclear/cytoplasm transport, chromatin remodeling and nuclear lamina formation. Our findings provide mechanistic insight for pathological accumulation of MSI/tau aggregates providing a potential basis for therapeutic interventions in neurodegenerative proteinopathies.
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-methyladenosine (m
A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m
A ...modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m
A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m
A coupled with ribosome profiling reveals that m
A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.
A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their ...malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD+/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.
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•AML cells proliferate in glucose-deprived environments with fructose supplementation•Fructose is mainly metabolized through hexokinase, not ketohexokinase, in AML cells•AML cells upregulate the serine synthesis pathway in fructose-rich environments•PHGDH inhibition in high-fructose conditions markedly reduces leukemia progression
Excessive fructose intake has been implicated in cancer progression, and Jeong et al. show an unexpected metabolism of fructose in cancer cells. Acute myeloid leukemic cells upregulate the serine synthesis pathway to metabolize fructose-derived carbons, and targeting PHGDH, a rate-limiting enzyme in the serine synthesis pathway, significantly reduces the tumor burden in the presence of high fructose.
In this issue of Cell Stem Cell, Shen et al. (2020) and Wang et al. (2020) independently identify the essential function of m6A demethylase ALKBH5 in maintaining myeloid leukemia stem cells. These ...studies expand the regulators of the epitranscriptome that are required for acute myeloid leukemia (AML) development.
In this issue of Cell Stem Cell, Shen et al. (2020) and Wang et al. (2020) independently identify the essential function of m6A demethylase ALKBH5 in maintaining myeloid leukemia stem cells. These studies expand the regulators of the epitranscriptome that are required for acute myeloid leukemia (AML) development.
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds ...directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
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-Methyladenosine (m
A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m
A dictates its diverse molecular and cellular effects in leukemias ...remains unknown. We found that YTHDC1 is the essential m
A reader in myeloid leukemia from a genome-wide CRISPR screen and that m
A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m
A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells. AML cells require the nYACs to maintain cell survival and the undifferentiated state that is critical for leukemia maintenance. Furthermore, nYACs enable YTHDC1 to protect m
A-mRNAs from the PAXT complex and exosome-associated RNA degradation. Collectively, m
A is required for the formation of a nuclear body mediated by phase separation that maintains mRNA stability and control cancer cell survival and differentiation.
Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic ...syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions.
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•Stage-specific iPSCs capture the clonal evolution of myeloid disease•Differentiation phenotypes show a graded progression to transplantable leukemia•CRISPR/Cas9 genome editing allows analysis of disease progression and reversal•Drug treatment analysis highlights stage-specific effects of candidate drugs
Kotini et al. integrate patient cell reprogramming with mutational analysis to assemble a panel of iPSCs capturing distinct stages across the spectrum of myeloid malignancy. They use these cells to map transformation into transplantable leukemia and study both disease progression via CRISPR/Cas9 genome editing and stage-specific effects of therapeutic agents.
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