"EZH2 is an accomplice" mycn carcinogenic driver outer week T cell lymphoma

Object -perimeter T cell lymphoma (PTCL) is a set of heresy blood cancer caused by the malignant conversion of mature T cells. Except for ALK -positive transgender large cell lymphoma (AlCl), PTCL patients are facing unfavorable prognosis, and about 75%of PTCL patients recur after first -line chemotherapy. Therefore, the 5-year survival rate is as low as 10-30%, which highlights the urgent needs for new treatment plans.

近日，比利时鲁汶大学（KU Leuven）的Daan Dierickx和Jan Cools团队在Blood期刊上发表题为Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T cell lymphoma 的文章，发现了MYC癌基因家族Member MyCN is a carcinogenic driver in PTCL, and identify EZH2 is an important auxiliary factor for the activation of the MYCN target transcriptional transcription, which can be used as the target of PTCL treatment.

In order to better understand the mechanism to promote the development of PTCL, the author first analyzes RNA sequencing of 28 PTCL samples, and found that 5 cases (18%) samples of MyCN are expressed. Combined with the PTCL dataset in public database Over -expression cases, Icn identified mycn as a new recurrence of cancer genes in PTCL, and found that about half of PTCL cases have high MyC characteristics, which shows that MyCN is abnormally expressed in PTCL and drives MyC target genetic characteristics.

In order to explore the carcinogenic potential of MYCN excessive expression in the body that drives T cell malignant tumors in the body, the author uses CRE -induced reverse virus carrier to combine the CD2 CRE or CD4 CRE genetically mice as a donor to simulate the MYCN expression in the lymphatic spectrum system to simulate T Cell lymphoma. Use RNA-SEQ to analyze the global gene expression separated CD4 T cells separated in the spleen of 6 model mice and 3 normal mice, revealing the genes of E2F and MyC in the genes driven by the mouse mycn lymphoma driven by the mouse MyCN lymphoma. The strong enrichment of the base order. Subsequently, chromatin immunization was performed, and the MYCN and various groups of protein labels were sequensed (Chip-seq). It was found that MyCN was most commonly combined in the starter area, and the binding site was rich in H3K4Me3 and H3K27ac. It shows that the development of T cell lymphoma in MYCN expresses the driving bone marrow transplant mouse model, MyCN is a strong cancer gene in the lymphic spectrum.

Further, EZH2 was found in the most significant MYCN direct target genes in the mouse model. EZH2 expression level in human PTCL with high MyC characteristics also increased, indicating that EZH2 is the transcription auxiliary factor of MyCN, and the methyl base of EZH2 Moving enzyme activity has not affected its transcriptional activity.

Finally, the author evaluated the treatment of T -cell lymphoma driven by MyCN -driven T cell lymphoma. The EZH2 selective degradant MS1943 was treated with lymphoma cell driven by MyCN, observing the strong dependence on EZH2. Similarly, the use of CDK1 inhibitors RO-3306 inhibits EZH2 phosphate on T487, induced apoptosis in MyCN-driven T cell lymphoma cells.

In summary, 5 of the 28 cases of PTCL cases discovered the expression of MYCN in 28 cases of PTCL cases. Integrating mice and human expression data to determine the key downstream target of EZH2 as MyCN. Auxiliary factor does not rely on EZH2's methyl metastase activity, but depends on the phosphorylation of CDK1. Mycn -driven T cell lymphoma is sensitive to EZH2 degradation or CDK1 inhibitory, EZH2 degradation or CDK1 inhibitory and HDAC inhibitory show the synergy effect.

Original link:

https://doi.org/10.1182/blood.2022016428

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