The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability

Abstract

N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics.

RNA binding protein IGF2BP1 meditates oxidative stress-induced granulosa cell dysfunction by regulating MDM2 mRNA stability in an m6A-dependent manner

“…In this study, we found the treatment of 3-nitropropionic acid (3-NP), a mitochondrial toxin inducing intracellular OS by targeting complex II of electron transport chain, led to significant downregulation of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and subsequently resulted in MDM2 mRNA instability in GCs. IGF2BP1 is an RNA-binding protein which preferentially binds to m 6 A modifications and helps to stabilize its targeted transcripts [ [15] , [16] , [17] , [18] ]. As a potent oncogenic factor, IGF2BP1 regulates proliferation, cell cycle progression and stemness of cancer cells [ 17 , 19 , 20 ].…”

m6A regulator-based methylation modification patterns and characterization of tumor microenvironment in acute myeloid leukemia

“…For example, VIRMA, which plays an oncogenic role in multiple human cancers ( Zhu et al, 2021 ), was more highly expressed in m6Acluster A compared with the other two clusters. Another gene with relatively higher expression in m6Acluster A-IGF2BP3-was recently found to be specifically overexpressed in AML and contributes to tumorigenesis and poor prognosis of this disease ( Zhang et al, 2022 ). These findings agreed favorably with the observed negative prognostic influence of m6Acluster A.…”

“…Methylation of N6 adenosine (m6A), which has been discovered as reversible RNA methylation affecting the regulation of post-transcriptional gene expression programs and protein production, is one of the most abundant internal marks on mammalian mRNA (Desrosiers et al, 1974;Fu et al, 2014;Zhao et al, 2017;Shi et al, 2019). The biological functions altered by m6A modifications are dynamically controlled by the m6A methyltransferase complex (writers), m6A demethylases (erasers), and m6A-binding proteins (readers) (Shi et al, 2019;Zaccara et al, 2019).…”

The Potential Value of m6A RNA Methylation in the Development of Cancers Focus on Malignant Glioma

“…FTO promoted leukemia oncogene mediated cell transformation and leukemia by reducing m6A levels in mRNA transcripts, inhibited all-trans retinoic acid (ATRA) induced AML cell differentiation, and modulated the expression of its target genes such as retinoic acid receptor alpha (RARA) and ankyrin repeat and SOCS box containing 2 (ASB2) ( 132 ). It has also been demonstrated that IGF2BP3 is required to maintain the survival of AML cells in an m6A-dependent manner and that IGF2BP3 functions to promote AML progression by interacting with RCC2 mRNA and stabilizing the expression of m6A-modified RNA ( 133 ). Studies have shown that overexpression of YTHDF2 in AML cells causes decreased half-life of a wide range of m6A transcripts, including TNF receptor superfamily member 2 (TNFRSF2) transcripts, which could help maintain the function of leukemic stem cells, and enhanced hematopoietic stem cell activity when YTHDF2 is knocked down ( 134 ).…”