HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA

Jiang, Feng-Jie; Tang, Xiaozhu; Tang, Chaohua; Hua, Zhen; Ke, Mengying; Wang, Chen; Zhao, Jiamin; Gao, Shengyao; Jurczyszyn, Artur; Janz, Siegfried; Beksaç, Meral; Zhan, Fenghuang; Gu, Chunyan; Yang, Ye

doi:10.1186/s13045-021-01066-6

Cited by 93 publications

(85 citation statements)

References 10 publications

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“…Dali et al (22) observed that YTHDF1-deficient mice presented an enhanced CD8+ T cell infiltration level and the improved therapeutic efficacy of PD-L1 checkpoint inhibitor. However, in MM, very few studies also have revealed the involvement of m6A-related genes in oncogenesis and progression at single gene level (23)(24)(25)(26). Research focusing on the systematic cognition of the role of m6A in the prognosis and immune microenvironment of MM is warranted.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of m6A RNA Methylation Regulators in the Prognosis and Immune Microenvironment of Multiple Myeloma

Liu

Shen

et al. 2021

Front. Oncol.

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BackgroundN6-methyladenosine is the most abundant RNA modification, which plays a prominent role in various biology processes, including tumorigenesis and immune regulation. Multiple myeloma (MM) is the second most frequent hematological malignancy.Materials and MethodsTwenty-two m6A RNA methylation regulators were analyzed between MM patients and normal samples. Kaplan–Meier survival analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were employed to construct the risk signature model. Receiver operation characteristic (ROC) curves were used to verify the prognostic and diagnostic efficiency. Immune infiltration level was evaluated by ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA).ResultsHigh expression of HNRNPC, HNRNPA2B1, and YTHDF2 and low expression of ZC3H13 were associated with poor survival. Based on these four genes, a prognostic risk signature model was established. Multivariate Cox regression analysis demonstrated that the risk score was an independent prognostic factor of MM. Enrichment analysis showed that cell cycle, immune response, MYC, proteasome, and unfold protein reaction were enriched in high-risk MM patients. Furthermore, patients with higher risk score exhibited lower immune scores and lower immune infiltration level.ConclusionThe m6A-based prognostic risk score accurately and robustly predicts the survival of MM patients and is associated with the immune infiltration level, which complements current prediction models and enhances our cognition of immune infiltration.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of m6A RNA Methylation Regulators in the Prognosis and Immune Microenvironment of Multiple Myeloma

Liu

Shen

et al. 2021

Front. Oncol.

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“…As referred above, m6A methylation is the widely popular modification in approximately 100 types of chemical modifications, and m6A modification has made significant contribution to the cancers progression. For example, as a crucial mA "reader," YTHDF1 aggravated the progression of cervical cancer through mA‐mediated up‐regulation of RANBP2, 24 HNRNPA2B1 induced multiple myeloma development by mediating ILF3 mRNA stabilization in a m6A‐dependent manner, 25 and METTL14 inhibited the tumor metastasis of hepatocellular carcinoma via modifying the m6A methylation of GFR/PI3K/AKT 26 . As a crucial m6A methylase, METTL3 has been indicated to involve in cancers progression via mediating cancer‐related proteins methylation level.…”

Section: Discussionmentioning

confidence: 99%

METTL3‐mediated m6A methylation of ASPM drives hepatocellular carcinoma cells growth and metastasis

Wang

Chen

et al. 2021

Clinical Laboratory Analysis

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Background Abnormal spindle‐like microcephaly (ASPM) has been proved to participate in tumor progression. However, the underlying mechanism of ASPM in liver hepatocellular carcinoma (LIHC) remains elusive. Methods The mRNA and protein expression were determined using Western blot and qRT‐PCR, and the capacities of cells proliferation, migration, and invasion were evaluated by CCK‐8, colony formation, wound healing, and transwell. MeRIP was performed to validate the interaction between ASPM and methyltransferase‐like 3 (METTL3). Results Herein, we found that ASPM was significantly upregulated in LIHC, and the high expression of ASPM was associated with poor LIHC prognosis. Furthermore, ASPM knockdown could suppress LIHC cells proliferation, migration, and invasion, while ASPM overexpression exerted reverse effect. Mechanistically, we revealed that the N6‐methyladenosine (m6A) modification of ASPM mRNA mediated by METTL3 promoted its expression in LIHC. More importantly, silencing METTL3 suppressed LIHC cells proliferation, migration, and invasion, which could be retained by ASPM overexpression. Conclusion Collectively, our findings suggested that METTL3/ASPM axis could serve as a novel promising therapeutic candidate for LIHC.

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“…Author details 1 Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, China. 2 School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China. 3 Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, Shanghai, China.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…Multiple myeloma (MM) is still an incurable hematological malignancy, as most of MM patients eventually relapse or become refractory [ 1 , 2 ]. Strikingly, the CAR-T cell therapy has achieved satisfactory efficacy in patients with relapsed or refractory MM in recent years [ 3 ].…”

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confidence: 99%

CAR-T therapy alters synthesis of platelet-activating factor in multiple myeloma patients

Kang²,

Yang

et al. 2021

J Hematol Oncol

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The chimera antigen receptor (CAR) T cell therapy is a novel and potential targeted therapy and has achieved satisfactory efficacy in patients with relapsed or refractory multiple myeloma (MM) in recent years. However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics. To explore the potential biomarkers in plasma for evaluating CRS and clinical efficacy, we performed metabolomic and lipidomic profiling of plasma samples from 17 relapsed or refractory MM patients received CAR-T therapy. Our study showed that glycerophosphocholine (GPC), an intermediate of platelet-activating factor (PAF)-like molecule, was significantly decreased when the participants underwent CRS, and the remarkable elevation of lysophosphatidylcholines (lysoPCs), which were catalyzed by lysoPC acyltransferase (LPCAT) was a distinct metabolism signature of relapsed or refractory MM patients with prognostic value post-CAR-T therapy. Both GPC and lysoPC are involved in platelet-activating factor (PAF) remodeling pathway. Besides, these findings were validated by LPCAT1 expression, a key factor in the PAF pathway, associated with poor outcome in three MM GEP datasets of MM. In conclusion, CAR-T therapy alters PAF synthesis in MM patients, and targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy.

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HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA

Cited by 93 publications

References 10 publications

Comprehensive Analysis of m6A RNA Methylation Regulators in the Prognosis and Immune Microenvironment of Multiple Myeloma

Comprehensive Analysis of m6A RNA Methylation Regulators in the Prognosis and Immune Microenvironment of Multiple Myeloma

METTL3‐mediated m6A methylation of ASPM drives hepatocellular carcinoma cells growth and metastasis

CAR-T therapy alters synthesis of platelet-activating factor in multiple myeloma patients

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