Transcriptome Profiling of N7-Methylguanosine Modification of Messenger RNA in Drug-Resistant Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological tumor caused by the malignant transformation of myeloid progenitor cells. Although intensive chemotherapy leads to an initial therapeutic response, relapse due to drug resistance remains a significant challenge. In recent years, accumulating evidence has suggested that post-transcriptional methylation modifications are strongly associated with tumorigenesis. However, the mRNA profile of m7G modification in AML and its role in drug-resistant AML are unknown. In this study, we used MeRIP-seq technology to establish the first transcriptome-wide m7G methylome profile for AML and drug-resistant AML cells, and differences in m7G between the two groups were analyzed. In addition, bioinformatics analysis was conducted to explore the function of m7G-specific methylated transcripts. We found significant differences in m7G mRNA modification between AML and drug-resistant AML cells. Furthermore, bioinformatics analysis revealed that differential m7G-modified mRNAs were associated with a wide range of cellular functions. Importantly, down-methylated m7G modification was significantly enriched in ABC transporter-related mRNAs, which are widely recognized to play a key role in multidrug resistance. Our results provide new insights into a novel function of m7G methylation in drug resistance progression of AML.

Identification and validation of a prognostic risk-scoring model for AML based on m7G-associated gene clustering

“…Chemotherapy remains the main option for most AML patients. Recent studies have shown that m 7 G-related regulators are highly expressed in AML and can affect the proliferation of leukemic stem cells; also, m 7 G mRNA modification levels are significantly elevated in drug-resistant AML cell lines ( 17 , 18 ). However, there is still a lack of studies of specific mechanisms by which m 7 G affects AML development and treatment, and its relevance to AML prognosis still needs further investigation.…”

“…METTL1 and WDR4 are significantly overexpressed in AML samples and knockdown of METTL1 effectively inhibits the growth of leukemic stem cells ( 17 ). A recent transcriptome-wide study of differential m 7 G methylationome profiling showed that drug-resistant AML cells had significantly different levels of m 7 G mRNA modification from AML cells and were significantly enriched in drug resistance-associated mRNA ( 18 ). These findings suggest that m 7 G methylation modifications have potential predictive value for the prognosis of AML.…”

The roles and therapeutic implications of messenger RNA internal N7‐methylguanosine and N6‐methyladenosine modifications in chemoresistance

“…p53, BRCA1) 4 . Additionally, a recent transcriptome‐wide profiling study of internal m 7 G revealed a significantly lower internal m 7 G level on ABC transporter‐encoded transcripts (key players in multidrug resistance) in drug‐resistant acute myeloid leukaemia (AML) cells than in regular AML cells 5 . Therefore, targeting the dysregulated m 6 A/m 7 G machinery appears to be a promising strategy to overcome cancer chemoresistance (Figure 1).…”

METTL1 mediated tRNA m 7 G modification promotes leukaemogenesis of AML via tRNA regulated translational control

“…N7-methylguanosine (m 7 G) modi cation occurred at tRNA G46, mRNA 5' cap and rRNAs [22]. Recent studies also report that a considerable m 7 G modi cation occurred at internal mRNAs [23][24][25]. The m 7 G modi cation is catalyzed by a highly conserved methyltransferase complex -methyltransferase like 1 (METTL1) and WD repeat domain 4 (WDR4) in mammalian [26,27].…”