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4661 Enhanced Expression of DNp73 Promotes Drug Resistance and Immune Evasion in Multiple Myeloma By Targeting the MYC and MYCN Pathways

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster III
Monday, December 11, 2023, 6:00 PM-8:00 PM

Lanting Liu1*, Lugui Qiu2, Zhen Yu, MD3* and Mu Hao3*

1Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical S, Tianjin, China
2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology& Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
3State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, CHN


Multiple myeloma (MM) is an incurable haematological malignancy with high chromosome instability and is highly dependent on the immunosuppressive bone marrow microenvironment. TP53 mutations and deletions are uncommon in MM patients, with other types of mechanisms involved in the abrogation of TP53 pathway activity. DNp73, an inhibitor of the p53 tumour suppressor family, drives drug resistance and cancer progression in several solid malignancies. However, the biological functions of DNp73, the molecular mechanisms underlying these actions and their correlations with aberrant TP53 expression in myelomagenesis remain unclear. In this study, we investigated the role of DNp73 in the drug resistance of MM, and disclosed the corresponding mechanism of how DNp73 promotes the immune escape of MM cells.


To disclose the role of DNp73 in promoting drug resistance and immune evasion in MM, and explore the therapeutic strategy based on the mechanism research.


We constructed DNp73 overexpression and sh-RNA interference plasmids to obtain stable cell lines. The effects of DNp73 on proliferation and drug sensitivity were determined by CCK8, flow cytometry and xenotransplantation model. To identify mechanisms of drug resistance, we here perform RNA-seq and CHIP-seq analyses in MM cell lines, while Western blot and RT-PCR were used to confirm the results. The DNA damage repair and invasion ability of MM cells were detected by immunofluorescence and transwell assay. To validate the role of DNp73 in immune escape, we also performed phagocytosis assays in vitro.


Our previous study revealed that the miRNA-15a is a tumour suppressor involved in aggressive MM cell proliferation and drug resistance. Here, we found that miRNA-15a downregulation in MM cells activated NF-κB-p65, which upregulated the expression of DNp73 at the transcriptional level. In addition, the level of miR-15a was negatively correlated with the expression of DNp73 in MM cells of patients (r=-0.672, p<0.05). Enforced expression of DNp73 promoted aggressive proliferation and multidrug resistance in MM cells (p<0.001). Bulk RNA sequencing data showed that the levels of MYCN, MYC and CDK7 were increased in cells with enforced DNp73 expression. Furthermore, a ChIP-qPCR assay revealed that DNp73 bound to the MYCN gene promoter and upregulated MYCN expression. The MM cell immune evasion rate was notable when DNp73 expression was high because of CD47 and PD-L1 upregulation. Blockade of the CD47/SIRPα and PD-1/PD-L1 signalling pathways by the SIRPα-Fc fusion protein IMM01 and monoclonal antibody atezolizumab significantly re-established the anti-MM function of macrophages and T cells in the MM microenvironment, respectively (p<0.01). Notably, DNp73 dysregulation and its pathogenetic function in MM cells were found to be independent of TP53 expression.


Altogether, our study demonstrates that DNp73 is a potential oncogene involved in MM pathogenesis and promotes MM cell proliferation and immune evasion by targeting the MYC and MYCN pathways.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH