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. 2025 Feb 13;25(1):253.
doi: 10.1186/s12885-025-13613-2.

Overexpression and oncogenic role of RIPK3 in acute myeloid leukemia associated with specific subtypes and treatment outcome

Yun Wang #  1   2   3   4 , Ting-Juan Zhang #  1   2   3   4 , Liu-Chao Zhang #  5 , Zi-Jun Xu  2   3   4   6 , Ming-Qiang Chu  1   2   3   4 , Yang-Jing Zhao  1   2   3   4   7 , Jiang Lin  2   3   4   6 , Jun Qian  1   2   3   4 , Jing-Dong Zhou  8   9   10   11
Affiliations

Overexpression and oncogenic role of RIPK3 in acute myeloid leukemia associated with specific subtypes and treatment outcome

Yun Wang et al. BMC Cancer. .

Abstract

Background: Receptor-interacting protein kinase 3 (RIPK3) has been implicated in the pathogenesis of diverse human cancers. However, the role of RIPK3 in acute myeloid leukemia (AML) is not fully understood, which needs further research and clarification.

Methods: We first identified the expression and clinical prognostic value of RIPK3 in AML through a public database and further validated in our research cohort. In addition, the biological function of RIPK3 in leukemic development was further verified through in vitro experiments.

Results: Based on the GEPIA database, we screened that RIPK3 overexpression among RIPK family was associated with poor prognosis in AML. Afterwards, another independent cohort from our research center further confirmed the expression pattern of RIPK3 in AML patients. Clinically, increased RIPK3 expression was closely related to specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation. The significant association of RIPK3 overexpression with FAB-M4/M5 was further validated in AML cell lines. Notably, AML patients with RIPK3 overexpression received transplantation presented a markedly longer survival than those just receiving chemotherapy, whereas those with RIPK3 underexpression showed similar survival between transplantation and chemotherapy group. Bioinformatics analysis showed the significant association of RIPK3 expression with diverse oncogenes/tumor suppressor genes and tumor-related biological processes in AML. Subsequently, we further performed functional experiments in vitro confirmed the potential oncogenic role of RIPK3 in AML.

Conclusions: Overexpression of RIPK3 was associated with specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation, and may facilitate the leukemic development. Moreover, RIPK3 overexpression was associated poor prognosis, and may guide treatment choice in AML.

Keywords: RIPK3; AML; Expression; Prognosis; Role.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The present study approved by the Ethics Committee of the Affiliated People’s Hospital of Jiangsu University (K-20230146-Y). The procedures used are consistent with the principles of the Helsinki Declaration. Written informed consents were obtained from all enrolled individuals prior to their participation. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Expression and correlation analysis of RIPK genes in AML. (a): RIPK1/RIPK2/RIPK3/RIPK4 expression in AML; (b): The correlations between each RIPK family member. *: P < 0.001. The expression of RIPK genes in AML patients compared with controls was analyzed by GEPIA (http://gepia.cancer-pku.cn/)
Fig. 2
Fig. 2
Prognostic value of RIPK genes in AML. The prognostic effect of RIPK genes (RIPK1/RIPK2/RIPK3) on overall survival and disease-free survival among total AML and non-M3 AML was analyzed by Kaplan-Meier method
Fig. 3
Fig. 3
Validation of RIPK3 expression and its discriminative capacity in AML. (a): RIPK3 expression in AML from our research cohort. (b): Receiver operating characteristic curve analysis of RIPK3 expression in distinguishing AML patients from controls
Fig. 4
Fig. 4
The associations of RIPK3 expression with specific subtypes of AML. (a): RIPK3 expression among different French-American-British (FAB) subtypes of AML. (b): RIPK3 expression among different karyotypic subgroups of AML. (c): RIPK3 expression among different cytogenetic risk groups of AML. (d): RIPK3 expression among different molecular risk groups of AML. (e): RIPK3 expression in groups of AML patients with and without NPM1 mutations. (f): RIPK3 expression in groups of AML patients with and without FLT3-ITD mutations. (g): RIPK3 expression in groups of AML patients with and without FLT3-TKD mutations. (h): RIPK3 expression in AML cell lines determined by real-time quantitative PCR. (i): RIP3 protein expression in several representative AML cell lines detected by western blot. *: P < 0.05; **: P < 0.01; ***: P < 0.001
Fig. 5
Fig. 5
The effect of transplantation on prognosis in RIPK3 over- and under-expression groups. The effect of transplantation on overall survival and disease-free survival in RIPK3 over- and under-expression groups was analyzed using the Kaplan-Meier method
Fig. 6
Fig. 6
Molecular signatures associated with RIPK3 expression in AML. (a): Expression heatmap of differentially expressed mRNAs/lncRNAs between low and high RIPK3 expression groups in AML (|log2 FC|>1.5, FDR < 0.05 and P < 0.05). (b): Volcano plot of differentially expressed mRNAs/lncRNAs between low and high RIPK3 expression groups in AML. (c): Gene Ontology (GO) analysis of differentially expressed mRNAs/lncRNAs. (d): Expression heatmap of differentially expressed miRNAs between low and high ID3 expression groups in AML (FDR < 0.05 and P < 0.05)
Fig. 7
Fig. 7
Validation of oncogenic role of RIPK3in AML. (a): Confirmation of RIPK3 expression knockdown by shRNA in both OCI-AML3 and NOMO-1 cell lines determined by real-time quantitative PCR. (b): Confirmation of RIPK3 expression knockdown by shRNA in both OCI-AML3 and NOMO-1 cell lines determined by western blot. (c): The effect of RIPK3 expression knockdown on cell proliferation in OCI-AML3 cell line. (d): The effect of RIPK3 expression knockdown on cell proliferation in NOMO-1 cell line. (e): The effect of RIPK3 expression knockdown on cell cycle in both OCI-AML3 and NOMO-1 cell lines. (f): The effect of RIPK3 expression knockdown on cell clonogenicity in both OCI-AML3 and NOMO-1 cell lines. (g): The effect of RIPK3 expression knockdown on cell migration ability in both OCI-AML3 and NOMO-1 cell lines
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