YTHDF2 in B-cell malignancies: a new path to enhanced immunotherapy

A new study by scientists at City of Hope in Los Angeles, California, sheds light on a new oncogenic pathway in B-cell malignancies. Their research is cellidentified the YTHDF2 enzyme as playing a key role in the development and progression of B-cell malignancies, such as B-cell acute lymphoblastic leukemia (B-ALL) and B-cell lymphoma. This discovery improves our understanding of the molecular mechanisms that drive these cancers and opens new possibilities for therapeutic intervention.

Dual role of YTHDF2: energy supply and immune evasion

At the heart of the study is the YTHDF2 enzyme, which the researchers describe as a “dual reader” for RNA modification. YTHDF2 plays a pivotal role in both promoting ATP synthesis and promoting immune evasion in malignant B cells. “YTHDF2 functions as a dual reader and stabilizes mRNA as a 5-methylcytosine (m5C) reader by recruiting PABPC1, thereby enhancing its expression and ATP synthesis,” said co-corresponding author Jianjun Chen. ” This mechanism is crucial for the rapid proliferation and survival of malignant B cells, which require an efficient energy supply to proliferate. ”

YTHDF2 also promotes immune evasion by destabilizing other mRNAs. N⁶ Methylacenosine (m⁶A) Reader.

One of the challenges in the treatment of blood cancers is the “antigen avoidance” of proteins essential for immune recognition, such as the CD19 protein and HLA-DMA/B. In 28-68% of cases, cancer cells reduce or lose CD19, making treatment less effective.

“We found that YTHDF2, as an m6A leader, also suppresses the expression of CD19 and HLA-DMA/B, allowing tumor cells to escape from attack by CAR-T cells,” explained first author Zhenhua Chen. . Through this dual function, YTHDF2 promotes immune evasion.

The discovery of the dual role of YTHDF2 in B-cell malignancies is part of a broader effort to understand the complex interplay of RNA modifications in cancer biology. RNA modifications such as m5C and m6A play important roles in regulating gene expression and cellular function. Proteins like YTHDF2 that recognize and interpret these modifications are emerging as important players in cancer development and progression.

Promising therapeutic target: YTHDF2 inhibitor CCI-38

The results of this study have important implications for the treatment of B-cell malignancies, especially in the context of chimeric antigen receptor (CAR)-T cell therapy. Although CAR-T cell therapy has been successful in achieving remission in many patients, long-term sustained remission remains a challenge due to antigen escape. Researchers' discovery that overexpression of YTHDF2 contributes to antigen avoidance provides a new target for therapeutic intervention.

The research team developed CCI-38, a small molecule inhibitor that targets YTHDF2. This inhibitor is expected to inhibit aggressive B-cell malignancies and increase sensitivity to CAR-T cell therapy. Jianjun Chen said, “Our compound CCI-38 has unique properties that selectively targets YTHDF2, enhances CD19 expression, and reduces tumor burden.” By inhibiting YTHDF2, CCI-38 not only restores antigen expression but also reduces energy supply to malignant cells, thereby increasing the efficacy of CAR-T cell therapy.

Implications for future research and clinical applications

The implications of this research extend beyond the immediate findings. The dual role of YTHDF2 in both energy metabolism and immune evasion highlights the complexity of cancer biology and emphasizes the need for multifaceted therapeutic approaches. Regarding B-cell malignancies, higher expression of YTHDF2 in malignant cells compared to healthy controls suggests that YTHDF2 may serve as a biomarker of disease progression and a potential target for therapeutic intervention. .

Researchers highlight the potential of YTHDF2 as a therapeutic target in B-cell malignancies and other types of cancers that rely on mitochondrial ATP synthesis.

Jianjun Chen said, “The dual-reader activity of YTHDF2 is critical for its pivotal oncogenic role in B-cell malignancies. Targeting this pathway could only improve treatment outcomes in B-cell malignancies. It also provides an opportunity to explore new treatments for other types of cancer.”

Furthermore, this study opens new avenues for optimizing CAR-T cell therapy. Co-treating patients with YTHDF2 inhibitors such as CCI-38 could potentially reduce the required CAR-T cell dose, thereby minimizing treatment-related toxicities and costs. There is. This approach could transform the treatment of relapsed or refractory B-cell malignancies and bring new hope to patients who have exhausted other treatment options.