Cell sub-journal: Zhang Haojian's team revealed the dynamic changes of m6A modification and the regulatory role and mechanism of PRMT6 in acute myeloid leukemia

Acute myeloid leukemia (AML) is a class of malignant hematologic tumors
caused by myeloid progenitor cell differentiation and malignant proliferation.
The accumulation of genetic or epigenetic changes converts normal hematopoietic stem/progenitor cells (HSPCs) into leukemia stem cells (LSCs), which initiates the development
of AML.
The clinical treatment of AML still faces great challenges, and at present, combination chemotherapy is mostly used, and the prognosis is poor, and the 5-year overall survival rate is less than 30%.

Therefore, it is urgent to deeply explore the pathogenesis of AML, find new therapeutic targets and explore new treatment strategies
.

The team of Zhang Haojian, Institute of Medical Research, Wuhan University/Center for Frontier Science of Immunology and Metabolism/School of Stomatology/Taikang Life Medical Center, published a research paper entitled: Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance in the journal Cell Stem Cell
。

This study decodes the dynamic changes of RNA m6A modification during AML, discovers the key molecule PRMT6, and elucidates its important role and mechanism in regulating AML development and LSC function, providing potential therapeutic strategies for the clinical treatment of
AML.

In this study, the research team decoded the RNA m6A modification omics of leukemia initiation cells (LICs) by MeRIP-seq sequencing method, and identified 3587 high-confidence m6A modification targets; Compared with the m6A modification group of normal hematopoietic stem progenitor cell population and combined with the expression level change analysis, it was found that m6A modification positively regulated the expression of stem cell self-renewal related genes during AML, suggesting that m6A participated in the stem acquisition of
leukemia-initiating cells.
Given that different reading proteins play an important role in the fate determination of m6A-modified mRNA, the research team used RIP-seq to analyze the targets of different reading proteins in leukemia-initiating cells
.

The study further focused on the reading protein IGF2BP2 and found that its expression was highly expressed in AML patient samples and was closely related to the poor prognosis of patients.
IGF2BP2 deletion promotes apoptosis, impairs leukemia stem cell function, and inhibits the development
of AML.
Interestingly, the research team found protein arginine methyltransferase PRMT6 in potentially key genes related to self-renewal in leukemia-initiating cells, confirming that IGF2BP2 recognizes PRMT6 mRNA stability regulated by IGF2BP2 and is a downstream functional target of
IGF2BP2.
The research team found that PRMT6 was highly expressed in AML samples and maintained leukemia stem cell function; PRMT6 knockout inhibits the development
of AML.

This study further confirmed that the PRMT6 inhibitor EPZ020411 can effectively inhibit leukemia stem cell function
.
Studies have shown that PRMT6 mainly catalyzes the formation
of inhibitory label H3R2me2a.
The research team discovered the lipid transporter MFSD2A of the key target gene downstream of PRMT6 by carrying out H3R2me2a ChIP-seq and integrating and analyzing RNA-seq
data.
It was confirmed that PRMT6 inhibits MFSD2A expression by catalyzing H3R2me2a modification, thereby regulating the transport of fatty acids such as docosahexaenoic acid DHA and maintaining leukemia stem cell function
.

In summary, this study analyzes the change law of RNA m6A modification during the occurrence of leukemia, clarifies the important function of PRMT6-MFSD2A signaling axis in regulating the stem maintenance of leukemia stem cells, and reveals the potential
of the PRMT6 inhibitor EPZ020411 to kill leukemia stem cells and inhibit the occurrence and development of AML.
This work will help us deeply understand the pathogenesis of AML, and will provide an important theoretical basis and new targeted strategies
for the clinical treatment of AML.

It is reported that the study is an in-depth study of the two works published by Zhang Haojian's team in Cell Stem Cell in
May 2020 and October 2021.

Cheng Ying, Gao Zhuying and Zhang Tiantian, doctoral students of the Center for Frontier Science of Immunology and Metabolism/Institute of Medical Research, Wuhan University, are the co-first authors of the paper, and Professor Zhang Haojian is the corresponding author
of the paper.
Professor Zhou Fuling of Zhongnan Hospital of Wuhan University and Professor Li Weiming of Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology provided important support
for this research.
The work was supported
by the Key R&D Program of the Ministry of Science and Technology, the Key Project and Youth Program of the National Natural Science Foundation of China, the Innovation Group of the Natural Science Foundation of Hubei Province, the Medical Take-off Program of Wuhan University, and the Independent Scientific Research Project of Central Universities.