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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207323 | GEO | 2022/07/04

REPOSITORIES: GEO

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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.

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

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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.

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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.

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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

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

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

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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

The m6A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPARγ

Project description:Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate pro-inflammatory (M1) versus pro-healing (M2) macrophages activation. Here, we observed that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) -deleted macrophages exhibited enhanced M1 phenotype and promoted DSS induced colitis development. However, the IGF2BP2-/- macrophages were refractory to IL4 induced activation and alleviated cockroach extract induced pulmonary allergic inflammation. Molecular studies indicated IGF2BP2 switched M1 macrophages to M2 activation by targeting tuberous sclerosis 1 (TSC1) via an N6-methyladenosine-dependent manner. Additionally, we also showed a signal transducer and activators of transcription 6 (STAT6) - high mobility group AT-hook 2 (HMGA2) -IGF2BP2-peroxisome proliferator activated receptor-γ (PPARγ) axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.

2021-03-15 | GSE162128 | GEO

Complete hematologic response of early-T-cell progenitor acute lymphoblastic leukemia to the gamma-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case

Project description:Notch pathway antagonists such as gamma-secretase inhibitors (GSI) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early-T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A. The three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient’s ETP-ALL from clonal hematopoiesis. Ex vivo culture of ETP-ALL blasts confirmed high levels of activated NOTCH1 that were repressed by GSI treatment, and RNA-Seq documented that GSI downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSI was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T cell type. H3K27ac superenhancer landscapes near MYC showed a pattern previously reported in acute myeloid leukemia (AML) that is sensitive to BRD4 inhibitors, and in line with this ETP-ALL blasts downregulated MYC in response to the BRD4 inhibitor JQ1. To our knowledge, this is the first example of complete response of a Notch-mutated ETP-ALL to a Notch antagonist and is also the first description of chromatin landscapes associated with ETP-ALL. Our experience suggests that additional attempts to target Notch in Notch-mutated ETP-ALL are merited. RNAseq and H3K27Ac ChIP seq of primary leukemic blasts treated in vitro with vehicle control or gamma-secretase inhibitor BMS-096024

2015-07-29 | E-GEOD-71414 | biostudies-arrayexpress

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