Expression of N6-Methyladenosine (m6A) Regulators Correlates With Immune Microenvironment Infiltration and Predicts Prognosis in Diffuse Large Cell Lymphoma (DLBCL)

Abstract Background: N6-methyladenosine (m6A) and immune microenvironment infiltration have been widely reported to play important roles in various cancers. However, in diffuse large cell lymphoma (DLBCL), the clinical significance of m6A regulators and their relationship with immune microenvironment infiltration have not been illuminated.Methods: The expression of m6A regulators in DLBCL was investigated using The Cancer Genome Atlas and Genotype-Tissue Expression databases. The capacity of m6A regulators in dividing molecular clusters of DLBCL was determined using Consensus Clustering algorithm and validated via principal component analysis. The clinical traits and prognosis difference in m6A-sorted clusters were revealed. The m6A prognostic signature was established and validated based on Gene Expression Omnibus dataset using univariate Cox and LASSO regression analysis. The immune cell infiltration and the expression of immune checkpoint genes in m6A low/high-risk DLBCL were studied. Gene set enrichment analysis (GSEA) was adopted to unveil the underlying molecular mechanism in m6A low/high-risk DLBCL.Results: Differentially expressed m6A regulators were able to molecularly discriminate DLBCL as two clusters based on consensus clustering and principal component analysis. A six m6A regulators-based risk prediction signature was established and validated as an independent predictor, which separated patients into m6A low- and high-risk groups. High-risk m6A indicates worse survival, for which the predictive AUC at 1-, 2-, and 5-year achieved 0.605, 0.640, and 0.652, respectively. Immune cell infiltration analysis revealed the B cells naïve and T cells gamma delta were the top increased and decreased immune cells in high-risk m6A patients. Up-regulated (PDCD1 and KIR3DL1) and down-regulated (TIGIT, DO1, and BTLA) immune checkpoint genes in high-risk m6A patients were identified. GSEA analysis unveiled high-risk m6A related to tumor proliferation associated process, while low-risk m6A related to defense response associated process. Conclusions: This study provided a comprehensive analysis for the clinical significance of m6A regulators and their association with immune microenvironment infiltration. An m6A regulators-based risk signature may be applied for the risk stratification of DLBCL patients, thus may facilitate the clinical management of DLBCL. Immune microenvironment was found to be closely related to m6A risk, which may be part of the mechanism of m6A regulators in DLBCL.

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BEAM chemotherapy and autologous haemopoietic progenitor cell transplantation as front-line therapy for high-risk patients with diffuse large cell lymphoma

British Journal of Haematology ◽

10.1046/j.1365-2141.1997.3833197.x ◽

1997 ◽

Vol 99 (2) ◽

pp. 379-385 ◽

Cited By ~ 20

Author(s):

Sergio Cortelazzo ◽

Andrea Rossi ◽

Piera Viero ◽

Piero Bellavita ◽

Roberto Marchioli ◽

...

Keyword(s):

High Risk ◽

Cell Transplantation ◽

Progenitor Cell ◽

Cell Lymphoma ◽

Large Cell ◽

Diffuse Large Cell Lymphoma ◽

Front Line ◽

Line Therapy ◽

Risk Patients ◽

Large Cell Lymphoma

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Intensified and high-dose chemotherapy with granulocyte colony-stimulating factor and autologous stem-cell transplantation support as first-line therapy in high-risk diffuse large-cell lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.2.491 ◽

1997 ◽

Vol 15 (2) ◽

pp. 491-498 ◽

Cited By ~ 38

Author(s):

U Vitolo ◽

S Cortellazzo ◽

A M Liberati ◽

R Freilone ◽

M Falda ◽

...

Keyword(s):

High Risk ◽

Cell Lymphoma ◽

Large Cell ◽

High Dose Chemotherapy ◽

High Dose ◽

Granulocyte Colony Stimulating Factor ◽

Diffuse Large Cell Lymphoma ◽

Free Survival ◽

Large Cell Lymphoma ◽

Stimulating Factor

PURPOSE In our previous study with MACOPB, we identified a high-risk group of patients with a poor 3-year survival rate of 29%. These patients were defined as having at diagnosis advanced-stage disease with high tumor burden (TB) and elevated lactate dehydrogenase (LDH) level or bone marrow (BM) involvement. A novel therapeutic scheme was investigated to improve the outcome of these patients. PATIENTS AND METHODS Fifty patients with high-risk diffuse large-cell lymphoma (DLCL) were enrolled. The therapeutic scheme includes three phases: induction with 8 weeks of MACOPB; intensification with a 3-day course of mitoxantrone 8 mg/m2 plus high-dose cytarabine (HDARA-C) 2 g/m2 every 12 hours plus dexamethasone 4 mg/m2 every 12 hours (MAD protocol) and granulocyte colony-stimulating factor (G-CSF) 5 microg/kg on days 4 to 17 to harvest peripheral-blood progenitor cells (PBPC); consolidation with carmustine (BCNU), etoposide, ARA-C, and melphalan (BEAM) regimen; plus autologous stem-cell transplantation (ASCT) with PBPC, marrow, or both. RESULTS Thirty-six patients (72%) achieved a complete response (CR), 11 (22%) showed no response (NR), and three (6%) died of toxicity. Among the 22 PRs or NRs after the induction phase, 56% of patients achieved a CR with subsequent intensified therapy. With a median follow-up duration of 32 months, the overall survival and failure-free survival rates were 56% and 50%, respectively. The disease-free survival rate is 69% at 32 months. Leukapheresis after MAD and G-CSF yielded a median of 32 x 10(6)/kg CD34+ cells and 80 x 10(4)/kg granulocyte-macrophage colony-forming units (CFU-GM). Thirty-nine patients were autografted and 11 did not undergo ASCT: six because of disease progression, four due to toxicity, and one because of patient refusal. The median times to achieve engrafment were 11 days (range, 7 to 19) to a neutrophil count greater than 0.5 x 10(9)/L and 12 days (range, 8 to 60) to a platelet count greater than 50 x 10(9)/L. CONCLUSION This sequential scheme with intensified and high-dose chemotherapy with ASCT is feasible with moderate toxicity and may improve the outcome in high-risk DLCL.

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