Dual RNA-binding of the YTHDF2 Protein in B Cell Cancers

While T cell-based immunotherapies have improved the treatment of several types of B-cell cancers, problems such as antigen escape and the rapid/efficient energy supply observed in malignant B cells represent significant barriers to durable disease remission. Interestingly, Yin et al. previously reported that B cells have the highest abundance of the m⁶a (N⁶-methyladenosine) modification of mRNA across the entire hematopoietic compartment. Among the “reader” proteins that bind to m⁶A-modified RNA, YTHDF2 (a YT521-B homology domain-containing family protein) recognizes and then destabilizes m⁶A-modified mRNAs by inducing mRNA decay and has critical roles in the development of cancer (Wang et al.).

A recent study from researchers led by Zhen-Hua Chen, Xiaolan Deng, and Jianjun Chen (Beckman Research Institute of City of Hope) sought to explore potential roles for i) YTHDF2 in recognizing and regulating the expression of mRNAs via m⁶A-independent mechanisms, and ii) the m⁶A machinery in the development of normal and malignant B cells. Encouragingly, their recent Cell article now demonstrates that YTHDF2 does indeed play a critical oncogenic role in the development of B-cell malignancies by providing an energy supply and supporting antigen escape through a newly described dual RNA-binding role (Chen, Zeng, Yang, and Che et al.).

The authors initially demonstrated that the YTHDF2 overexpression observed in B-cell malignancies was driven by the activity of oncogenic transcription factors such as MYC, STAT3, and POU2AF1, which act on the regulatory regions of the YTHDF2 gene. Furthermore, they discovered that YTHDF2 overexpression alone sufficed to induce the malignant transformation of normal precursor B cells and to cause precursor B-cell acute lymphoblastic leukemia in vivo.

Their data suggested that YTHDF2 plays a pivotal pro-tumorigenic role in B-cell cancer development/progression beyond its m⁶A-reading activity, and, as such, they established that YTHDF2 functioned as a dual reader in this context. In the first case, YTHDF2 promoted immune evasion via antigen escape by destabilizing mRNAs encoding CD19 and HLA-DMA/B (major histocompatibility complex class II molecules) by functioning as an m⁶a reader. However, they discovered that YTHDF2 also stabilized other mRNAs (such as those encoding F-type ATPase subunits) as an m⁵C (5-methylcytosine) reader, which employed the same binding “pocket” but a different selection of amino acid residues. In this case, YTHDF2 recruited the mRNA stabilizer PABPC1 (Poly(A) Binding Protein Cytoplasmic 1) (Yang et al.) to enhance their expression and increase ATP synthesis and cell metabolism. Interestingly, the same set of oncogenic transcription factors that induced YTHDF2 overexpression also induced PABPC1 overexpression.

Of additional therapeutic interest, the study highlighted the ability of YTHDF2 depletion or pharmacological YTHDF2 inhibition by CCI-38 treatment to suppress aggressive B-cell malignancies and to sensitize these cells to T cell-based immunotherapy (such as chimeric antigen receptor T cell therapy or a bispecific T cell engager).

Overall, this exciting new study found that overexpression of YTHDF2 - which has a dual role in regulating mRNA biology by binding to two distinct types of mRNA modifications - supports the initiation, progression, and immune evasion of B-cell cancers. As such, they highlight a combination of the small-molecule inhibitor CCI-38 and T cell therapies as an exciting approach to safely and effectively treat B-cell cancers. However, the authors do note the need to clear up some remaining questions; these include i) deciphering how YTHDF2 recruits distinct co-factors and induces distinct biological consequences when binding to m⁶A- vs. m⁵C-modified target mRNAs; and ii) evaluating whether the discovered phenomenon also takes place on other types of normal cells and cancers.

The YTHD pathway, which encompasses the cellular signaling and regulatory processes mediated by YTH-domain proteins, is a central component of the m⁶a RNA modification system, in which YTH-domain proteins function as readers that recognize m⁶A-modified RNA to regulate stability, splicing, translation, and decay. m⁶a constitutes the most abundant internal modification in eukaryotic mRNA, interpreted primarily by proteins such as YTHDF1–3 and YTHDC1–2. Of note, the dysregulation of these proteins has been linked to cancer, metabolic disorders, infertility, and neurological diseases.

Of particular interest, this fascinating study employed several products from Active Motif, including recombinant YTHDF1, YTHDF2, and YTHDF3 proteins, as well as the ChIP-IT^® Express Chromatin immunoprecipitation kit. Active Motif remains the industry leader in developing and delivering innovative tools to enable epigenetics and gene regulation research; whether you are an expert in the field or a researcher interested in integrating epigenetics into your studies for the first time, Active Motif´s portfolio of epigenetics-related products and the support of our experts will provide you with complete and innovative solutions to tackle your scientific inquiries. Furthermore, Active Motif´s suite of Epigenetic Services can accelerate your research through the expertise of our epigenetic experts.