IGF2BP3 As an N6-Methyladenosine Reader Promotes Acute Myeloid Leukemia Progression By Regulating the Stability of Target RNA

Background: N6-methyladenosine (m6A) is the most common post-transcriptional modification of eukaryotic mRNA. 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), which constitutes a subtype of this malignancy associated with poor prognosis and high genetic risk.

Methods: Bioinformatics analysis of public databases was performed to screen the differentially expressed m6A regulators in AML. Clinical samples were collected to detect the expression of IGF2BP3 in AML by RT-qPCR. The effects of IGF2BP3 on the proliferation, apoptosis and cycle of AML cells were detected by CCK-8 and flow cytometry. RNA-seq was used to identify target genes of IGF2BP3 by integrating analysis with RIP-Seq, iCLIP-Seq and MeRIP-Seq data sets.

Results:High expression of IGF2BP3 is closely associated with poor prognosis of AML and is higher in patients with high genetic risk group. IGF2BP3 was the lowest expressed in AML-M3 and the highest expressed in RUNX1 mutant type. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 suppressed dramatically induces apoptosis, reduces proliferation and impaired leukemic capacity AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-tagged RNA.

Conclusions:We provided compelling evidence to demonstrate that m6A reader IGF2BP3 contributed to tumorigenesis and poor prognosis of AML, which can serve as a target to develop therapeutics for cancer treatment.

Disclosures

No relevant conflicts of interest to declare.