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    Home > Active Ingredient News > Blood System > Blood | Zhang Haojian's team reveals the molecular mechanism of RNA binding protein YBX1 in acute myeloid leukemia​

    Blood | Zhang Haojian's team reveals the molecular mechanism of RNA binding protein YBX1 in acute myeloid leukemia​

    • Last Update: 2021-04-19
    • Source: Internet
    • Author: User
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    Acute myeloid leukemia (AML) is the most common hematological malignancy, manifested by the differentiation of myeloid progenitor cells, malignant proliferation and impaired production of normal blood cells.

    AML is still the deadliest hematological tumor and is prone to relapse and drug resistance, which has brought great troubles to clinical treatment.

    Therefore, studying the pathogenesis of AML and exploring new therapeutic targets is one of the key scientific issues in this field.

    RNA-binding proteins (RBPs) are proteins that can bind to double-stranded or single-stranded RNA.
    They are widely involved in RNA transcription and post-transcriptional regulation, including splicing, modification, nuclear export, localization, stability, degradation, and translation.
    Play a key role in the decision of fate.

    More and more studies have shown that RBPs participate in the regulation of cell homeostasis under normal physiological and pathological conditions, and play an important role in tumorigenesis and development [1].

    Recent studies have gradually revealed the role of some RBPs in blood physiology and pathology [2,3], but for most RBPs, whether it affects the occurrence and development of AML, its role and mechanism is still poorly understood.

    Recently, the team of Professor Zhang Haojian of Wuhan University published an online article titled "YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A manner" in Blood magazine.

    The study found that the RNA binding protein YBX1 regulates the survival of myeloid leukemia cells and is essential for the occurrence and development of AML, but does not affect normal hematopoietic and hematopoietic stem cell functions.

    In-depth mechanism studies have found that YBX1 and IGF2BPs act synergistically to stabilize m6A-labeled mRNA, thereby regulating the expression levels of MYC and BCL2 in AML cells.

    In this study, the researchers found and confirmed the significant high expression of YBX1 through a comprehensive analysis of the currently known expression levels of RBPs-related mRNA in AML patient cells.

    YBX1 (Y box binding protein 1) is a multifunctional RNA/DNA binding protein with a conserved cold shock protein domain (CSD), and is involved in cell apoptosis and proliferation, mRNA splicing, translation, DNA damage repair, differentiation and response Stimulus and other physiological processes.

    But its role in AML is unclear.

    In view of this, the researchers used shRNA interference technology to knock down YBX1 in primary leukemia cells and cell lines derived from AML patients, and found that YBX1 deletion significantly inhibited cell proliferation and colony formation, and promoted leukemia cell differentiation and apoptosis.

    To further study the function of YBX1 in AML in vivo, the researchers constructed conditional knockout mice and established a mouse model of AML induced by the classic MLL-AF9 fusion gene.
    At the same time, they used the human xenograft (PDX) model of AML to develop A series of studies have been conducted.

    It was found that YBX1 deletion significantly inhibited the occurrence and development of AML.

    Interestingly, the researchers found that the absence of YBX1 has no significant effect on normal hematopoietic and normal hematopoietic stem cell function.

    In order to further explore the mechanism of YBX1 in AML, researchers used various molecular and biochemical experimental methods, combined with technical methods such as RNA-seq, RIP-seq, SLAM-seq and m6A-seq, and found and confirmed that YBX1 is mainly through Its CSD region interacts with RNA m6A modified reading molecule IGF2BPs, binds and stabilizes m6A modified mRNA, and acts as a stabilizer.

    The researchers also found that YBX1 regulates the expression of apoptosis-related genes, and confirmed that YBX1 mainly affects the mRNA stability of MYC and BCL2, and does not affect their transcription and shearing.

    They can significantly restore the function of AML cells by replenishing MYC or BCL2, thus confirming that MYC and BCL2 are downstream targets of YBX1 and mediate its role in AML.

    In summary, this study reveals the role and mechanism of YBX1 in specifically regulating AML, laying a theoretical foundation for exploring new intervention strategies, and has important application value for the clinical treatment of AML.

    It is reported that during the revision process of this article, Nature published research work from the team of Professor Florian Heidel in Germany and the team of Professor Matthias Mann, revealing the important role of YBX1 in myeloproliferative tumor MPN.
    At the same time, it was also found that YBX1 deletion does not affect normal hematopoiesis.
    (NaturemRNA splicing factor YBX1 mediates the persistence of JAK2 mutant tumors) [4].

    It can be said that the two articles together uncovered the new functions and new mechanisms of YBX1 in blood physiology and pathology.

    Professor Zhang Haojian from Wuhan University Medical Research Institute/Frontier Science Center of Immunity and Metabolism is the corresponding author of this article.
    PhD students Feng Mengdie, Xie Xueqin, and Han Guoqiang are the co-first authors of this article.

    Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
    Personal forwarding and sharing are welcome.
    Reprinting is prohibited without permission.
    The author has all legal rights and offenders must be investigated. Original link: https://doi.
    org/10.
    1182/blood.
    2020009676 Plate maker: Qi sauce reference [1] Hentze MW, Castello A, Schwarzl T, Preiss T.
    A brave new world of RNA-binding proteins.
    Nat Rev Mol Cell Biol.
    2018;19(5):327-341.
    [2] Hodson DJ, Screen M, Turner M.
    RNA-binding proteins in hematopoiesis and hematological malignancy.
    Blood.
    2019;133(22):2365-2373.
    [3] Wang J, Li Y, Wang P, et al.
    Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis.
    Cell Stem Cell.
    2020;27(1):81-97.
    [4 ] Jayavelu AK, Schnoder TM, Perner F, et al.
    Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms.
    Nature.
    2020;588(7836):157-163.
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