![]() IGF2BP2-bound RNA was isolated from immunoprecipitated anti-IGF2BP2 antibody using TRIzol (Invitrogen). IRIP-seq library preparation and sequencing In addition, we identified the small molecule JX5 as an IGF2BP2 inhibitor that prevented T-ALL leukemogenesis. Further analysis showed that IGF2BP2 could directly bind NOTCH1 and stabilize NOTCH1 mRNA in an m 6A-dependent manner. ![]() Here we found that IGF2BP2 promoted human T-ALL growth, reduced cytarabine (Ara-C)-, vincristine (VCR)-, venetoclax- or dexamethasone (Dex)-induced apoptosis in vitro and is essential for leukemogenesis in vivo. While great effort has been expanded to explore the function of m 6A modifications in acute myeloid leukemia, knowledge regarding the role of IGF2BP2 in T-ALL is limited. showed that the KH domains, especially the KH3-4 di-domain, are critical for the binding of IGF2BP2 to m 6A-modified RNAs. The KH domains are responsible for the recognition and binding of some specific mRNAs, including ACTIN, MYC and IGF2. IGF2BP2, as an m 6A “reader”, binds RNA through six RNA-binding domains, two of which contain RNA recognition motifs (RRM1 and RRM2) and four KH domains (KH1-KH4). In addition, the m 6A modification relies on “readers” to exert its biological function. The methyltransferase complex, which includes the methyltransferase-like 3 and 14 proteins (METT元 and METTL14) and their regulator Wilms tumor 1-associated protein (WTAP), deposits m 6A modification, which is then removed by the following “erasers” demethylases: fat mass and obesity-associated protein (FTO) and ketoglutarate- dependent dioxygenase AlkB homolog 5 (ALKBH5). Posttranscriptional modifications of mRNAs, including N6-methyladenosine (m 6A), which is the most common internal RNA modification, is well known for regulating gene expression by altering mRNA splicing, stability, translocation, and translation. Thus, the identification of other NOTCH1 related genes has become a major priority for the development of anti-NOTCH1 therapies in the clinic. Nevertheless, inhibiting NOTCH1 signaling using γ‑Secretase inhibitors (GSI) has demonstrated poor efficacy in the clinical treatment of T-ALL. ![]() Aberrant constitutively active NOTCH1 upregulates anabolic pathways and oncogene MYC expression, which promote T cell leukemogenesis. The activation of the NOTCH1 pathway is essential for early T cell fate determination in the haematopoietic system. NOTCH1 activation is triggered by interaction with its ligands, which are members of the Delta and Jagged families and are expressed on neighboring cell surfaces. This clinical challenge has led researchers to decipher the molecular mechanism of T-ALL transformation and progression and develop alternative drugs to treat this malignancy.Ī genome-wide association study of T-ALL cases has identified considerable gene mutations among them the key oncogenic regulator is NOTCH1, which is found in more than 60% of T-ALL. ![]() Although the current cure rates increased to 80% in children and 60% in adults, patients with primary resistant T-ALL frequently fail to obtain a complete hematological remission or relapse after the initial response. T-ALL originates from genomically altered and/or epigenetically changed transformation of immature T cells. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological neoplasm that frequently occurs in children and adolescents worldwide.
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