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Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

ABSTRACT: Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

PROVIDER: PRJNA846158 | ENA |

REPOSITORIES: ENA

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Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant leukemia with extreme limited treatment for relapsed patients. N6‐methyladenosine (m6A) reader Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) participates in the initiation and growth of cancers by communicating with various targets. Here, we found IGF2BP2 is highly expressed in T-ALL. Gain and loss of IGF2BP2 demonstrated IGF2BP2 was essential for T-ALL cell proliferation in vitro and loss of IGF2BP2 prolonged animal survival in a human T-ALL xenograft model. Mechanistically, IGF2BP2 directly bound to T-ALL oncogene NOTCH1 via an m6A dependent manner. Furthermore, we identified a small-molecule IGF2BP2 inhibitor JX5 and treatment of T-ALL with JX5 showed similar functions as knockdown of IGF2BP2. These findings not only shed light on the role of IGF2BP2 in T-ALL, but also provide an alternative γ‑Secretase inhibitors (GSI) therapy to treat T-ALL.

2022-07-04 | GSE207323 | GEO

Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

Project description:N6-methyladenosine (m6A) reader Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) participates in the initiation and growth of cancers by communicating with various targets. Here, we found IGF2BP2 is highly expressed in T-ALL. Gain and loss of IGF2BP2 demonstrated IGF2BP2 was essential for T-ALL cell proliferation in vitro and loss of IGF2BP2 prolonged animal survival in a human T-ALL xenograft model. Mechanistically, IGF2BP2 directly bound to T-ALL oncogene NOTCH1 via an m6A dependent manner.

2022-09-15 | GSE205503 | GEO

Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

Project description:Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

| PRJNA854806 | ENA

The m6A Reader IGF2BP2 Regulates Glutamine Metabolism and Represents a Therapeutic Target in Acute Myeloid Leukemia [Ribo-seq]

Project description:We report that m6A reader IGF2BP2 participates in the regulation of glutamine metabolism in AML. To further clarify whether IGF2BP2 knockdown (KD) leads to translational inhibition, we perform Ribo-seq in control and IGF2BP2 KD cells.

2022-11-01 | GSE211618 | GEO

The m6A Reader IGF2BP2 Regulates Glutamine Metabolism and Represents a Therapeutic Target in Acute Myeloid Leukemia [RNA-seq]

Project description:We report that m6A reader IGF2BP2 participates in the regulation of glutamine metabolism in AML. Targeting IGF2BP2 with our developed inhibitor CWI1-2 shows promising therapeutic efficacy in AML.To explore the mechanism of the inhibitor, we performed RNA-seq in AML cells upon treatment with CWI1-2 or DMSO. On the other hand, to distinguish the mechanism between IGF2BP2 and YTHDF2, we compare RNA-seq data of IGF2BP2 KD with YTHDF2 KD.

2022-11-01 | GSE199204 | GEO

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [IGF2BP2 RNA-seq]

Project description:Our data reveal that RNA m6A displays a sharp transition during leukemogenesis and involves in acquiring stem cell properties of leukemia stem cells (LSCs). We find that m6A reader IGF2BP2 and protein arginine methyltransferase PRMT6 play key roles in the acquisition of LSCs properties. Genetical deletion and pharmacological inhibition of PRMT6 delayed AML development. Mechanistically, IGF2BP2 regulates PRMT6 expression by stabilizing its mRNA in an m6A-dependent manner. PRMT6 further suppresses the expression of lipid transporter MFSD2A by establishing inactive H3R2me2a in its promoter region. Loss of PRMT6 and IGF2BP2 upregulates the expression of MFSD2A that increases the uptake of docosahexaenoic acid. Collectively, our findings uncover a critical role of IGF2BP2-PRMT6-MFSD2A signaling axis in AML development, and provide a promising therapeutic strategy for targeting LSCs.

2023-06-20 | GSE210278 | GEO

Structural basis of YTH domain as m6A reader

Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader. PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) was applied to human YTHDC1 protein to identify its binding sites.

2014-09-18 | E-GEOD-58352 | biostudies-arrayexpress

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [MeRIP-seq]

2023-06-20 | GSE210280 | GEO

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [Prmt6 RNA-seq]

2023-06-20 | GSE210279 | GEO

Landscape of m6A modification in haematopoietic system unveils an essential role of IGF2BP2 in preserving haematopoietic stem cell function

Project description:N6-methyladenosine (m6A) is an abundant modification on mRNA, and plays critical functions in various cellular processes, including cell fate determination and lineage transition. However, the landscape and dynamics of m6A modification in haematopoietic system remain unknown. Here, we delineate a comprehensive m6A landscape across haematopoietic hierarchy and uncover that IGF2BP2 is required for preserving haematopoietic stem cells (HSCs) function. Our data reveal a marked cell-type- and haematopoietic-lineage-specific m6A landscape. Intriguingly, most m6A modifications arise in the early stat of haematopoiesis, and are critical in defining cellular states of HSCs. Moreover, m6A modification is the major factor in determining mRNA abundance in HSCs. Importantly, we find that higher expression of m6A reader IGF2BP2 is critical in controlling gene expression states and the functional maintenance of HSCs. IGF2BP2 deficiency induces apoptosis and quiescence loss, and substantially impairs the reconstitution capacity of HSCs. In addition, deletion of IGF2BP2 increases the mitochondrial activity of HSCs. Mechanistically, IGF2BP2 stabilizes Bmi1 mRNA in an m6A-dependent manner, which represses the expression of mitochondria-related genes. Collectively, our results present a fascinating portrait of m6A modification during haematopoiesis, and uncover a key role of IGF2BP2 in maintaining HSCs function by regulating Bmi1 stability and restraining mitochondrial activity.

2021-10-26 | GSE165863 | GEO

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