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iNature
N6-methyladenosine (m6A) modification plays a key role in regulating mRNA fate and is involved in various physiological and pathological processes, including tumorigenesis.
Thesem6Aregulatory proteins have been shown to play a key carcinogenic role in various types of cancer, including acute myeloid leukemia (AML).
IGF2BP2 has recently been reported as anm6A-bindingprotein that enhances mRNA stability and translation
.
However, its role in AML remains largely unknown
.
On October 27, 2022, Professor Weng Zhenyou of Guangzhou Laboratory, Professor Chen Jianjun of City of Hope, Huang Huilin, researcher of Sun Yat-sen University Cancer Prevention and Treatment Center, and Professor Wei Minjie of China Medical University jointly published an online publication in Cancer Cell magazine entitled " The m6A Reader IGF2BP2 Regulates Glutamine Metabolism and Represents a Therapeutic Target in Acute Myeloid Leukemia", which reports on the carcinogenic effects and therapeutic targeting of
IGF2BP2 in AML.
In AML, high expression of IGF2BP2 is associated
with poor prognosis.
IGF2BP2 promotes the development of AML and the self-renewal
of leukemia stem/initiation cells in anm6A-dependentmanner by regulating the expression of key targets in the glutamine metabolic pathway, such as MYC, GPT2, and SLC1A5.
Inhibition of IGF2BP2 by a recently discovered small molecule compound (CWI1-2) shows promising anti-leukemic effects
in vivo and in vitro.
Together, the results reveal the role of IGF2BP2 andm6Amodifications in amino acid metabolism and highlight the potential of
targeting IGF2BP2 as a promising AML therapeutic strategy.
as therapeutic targets.
m6Alabeling on mRNA is primarily catalyzed by a methyltransferase complex consisting of METTL3/METTL14/WTAP cores and other cofactors that can be cleared
by demethylase proteins such as FTO or ALKBH5.
Similar to epigenetic modifications to DNA and histones, the role of m6A modifications is dependent on effector proteins, i.
e.
,m6A"barcoder" proteins
.
As the firstm6A-bindingprotein to be discovered, YTHDF2 unstable mRNA modified mRNA and is required for
AML initiation and propagation.
Nevertheless, by analyzing m6A sequencing (m6A-seq) data at FTO overexpression or METTL14 knockout (KD), it was found that many of the downregulated transcripts were alsom6Ahypomethylated, indicating that these transcripts were recognized
by a reader protein other than YTHDF2.
In fact, a new class of m6A-binding proteins, the IGF2BP protein family, has been discovered, which stabilizes mRNA containingm6Aand facilitates its translation
through its homology domain.
The carcinogenic effects of IGF2BP are mainly studied in
solid tumors.
However, little
is known about the function and therapeutic potential of IGF2BP protein in AML, especially as anm6Areader.
As a hallmark of cancer, reprogrammed energy metabolism maintains the growth and proliferation
of tumor cells.
Glutamine (Gln) is an important energy source that is transported into cells and converted into glutamate (Glu), which is then used to produce α α-ketoglutarate (α-KG), fuel the tricarboxylic acid (TCA) cycle, or as a precursor to other amino acids, glutathione and nucleotides
.
AML is the deadliest subtype of leukemia with the lowest 5-year overall survival rate (< 30%)
.
Inhibition of Gln uptake and metabolism appears to be an attractive strategy
for treating AML cells in vitro and mouse models.
However, in AML, whetherm6Aregulates Gln metabolism is unclear
.
In this study, the researchers reported that IGF2BP2 andm6Amodifications are involved in the regulation
of Gln uptake and metabolism in AML.
IGF2BP2 is overexpressed in AML, especially in leukemiastem/initiating cells (LSCs/LICs), and its increased expression is associated
with poor prognosis in AML patients.
The silencing of IGF2BP2, or the deletion of METTL3 or METTL14, leads to significant reprogramming of cellular metabolites, especially those involved in Gln and Glu metabolism, and leads to inhibition
of mitochondrial activity and ATP production in AML cells.
Further studies have shown that the stable and enhanced translation ofm6A-modifiedtarget transcripts in the IGF2BP2-mediated Gln metabolic pathway, including MYC, SLC1A5 and GPT2, is essential
for the development of LSCs/LICs and AML.
In addition, researchers have developed a potent small molecule inhibitor (i.
e.
, CWI1-2) that preferentially binds IGF2BP2 and inhibits its interaction
withm6A-modifiedtarget transcripts.
The use of CWI1-2 targeting IGF2BP2 alone, or in combination with other drugs such as daunorubicin (DNR) or perharringrbase (HHT) has shown good therapeutic results
.
In summary, this study demonstrates the important role of IGF2BP2 as anm6A-bindingprotein in controlling Gln metabolism during the pathogenesis of AML, highlighting that targeting IGF2BP2 is an effective therapeutic strategy
for AML and other types of IGF2BP2 overexpression cancers.
Original link: https://doi.
org/10.
1016/j.
ccell.
2022.
10.
004
—END—
The content is 【iNature】
