Dear Editor,Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease, 1 and the high-throughput sequencing has facilitated our understanding of genetic aberrations in DLBCL. [2][3][4] The proviral integration site for Moloney murine leukemia virus 1 (PIM1), which encodes serine/threonine protein kinase, is identified as a target of aberrant somatic hypermutation in DLBCL 5 and involved in tumorigenesis in hematopoietic malignancies 6,7 and solid cancers. 8 Recent studies have revealed PIM1 mutation frequencies ranging from 20 to 30%. 9,10 However, there are few studies focused on its genetic alterations, molecular profiles, drug responses, and clinical significance. Here, we integrated targeted sequencing and transcriptome analysis to explore the pathogenic role of PIM1 mutations and as a personalized therapeutic target in PIM1-mutated DLBCL patients.A total of 188 patients underwent targeted sequencing using a 307 lymphoma-related gene panel, and 162 patients were included in the analysis. A workflow chart is presented in Figure S1. Baseline characteristics are found in Table S1, and all variants identified are described in Table S2. See detailed methods in the Supporting Information. We found PIM1 to be mutated in 46 (28.4%) patients (Figure 1A), with 164 genetic alterations (Table S3). Variant classifications showed that missense mutations occurred most frequently (84.1%); almost half of them (48.7%) are predicted to be deleterious (SIFT score < .05) (Figure 2A,B and Table S4). Besides, the C>T transition was the predominant type (54.4%) (Figure 2C). Of the 46 mutant patients, all samples harboured nonsynonymous alterations, with more than three mutations detected in a single sample from half of the patients (Figure 2D). We observed exon 4 to most often be mutated, and 57% (84/164) of mutations are located in the serine/threonine protein kinase domain (Figure 2E). Comutation and mutual exclusivity analysis identified 72 statistically significant interaction pair genes This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. To assign patients into different risk categories, cytogenetic abnormalities and genetic mutations have been widely applied to the prognostic stratification of DLBCL. Increasing evidence has demonstrated that deregulated epigenetic modifications and long noncoding RNAs (lncRNAs) contribute to the initiation and progression of DLBCL. However, specific lncRNAs that affect epigenetic regulation and their value in predicting prognosis and therapy response remain uncertain. Here, 2,025 epigenetic-related genes were selected, and 9 lncRNAs (PRKCQ-AS1, C22orf34, HCP5, AC007389.3, APTR, SNHG19, ELFN1-AS1, LINC00487, and LINC00877) were tested and validated to establish an lncRNA-regulating epigenetic event signature (ELncSig). ELncSig, which was established based on independent lymphoma datasets, could distinguish different survival outcomes. Functional characterization of ELncSig showed that it could be an indicator of the immune microenvironment and is correlated with distinctive mutational characteristics. Univariate and multivariate analyses showed that ELncSig was independent of traditional prognostic factors. The novel immune-related ELncSig exhibits promising clinical prognostic value for DLBCL.

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PurposeAlthough the role of tumor-infiltrating T cells in follicular lymphoma (FL) has been reported previously, the prognostic value of peripheral blood T lymphocyte subsets has not been systematically assessed. Thus, we aim to incorporate T-cell subsets with clinical features to develop a predictive model of clinical outcome.MethodsWe retrospectively screened a total of 1,008 patients, including 252 newly diagnosed de novo FL patients with available peripheral blood T lymphocyte subsets who were randomized to different sets (177 in the training set and 75 in the internal validation set). A nomogram and a novel immune-clinical prognostic index (ICPI) were established according to multivariate Cox regression analysis for progression-free survival (PFS). The concordance index (C-index), Akaike’s information criterion (AIC), and likelihood ratio chi-square were employed to compare the ICPI’s discriminatory capability and homogeneity to that of FLIPI, FLIPI2, and PRIMA-PI. Additional external validation was performed using a dataset (n = 157) from other four centers.ResultsIn the training set, multivariate analysis identified five independent prognostic factors (Stage III/IV disease, elevated lactate dehydrogenase (LDH), Hb &lt;120g/L, CD4+ &lt;30.7% and CD8+ &gt;36.6%) for PFS. A novel ICPI was established according to the number of risk factors and stratify patients into 3 risk groups: high, intermediate, and low-risk with 4-5, 2-3, 0-1 risk factors respectively. The hazard ratios for patients in the high and intermediate-risk groups than those in the low-risk were 27.640 and 2.758. The ICPI could stratify patients into different risk groups both in the training set (P &lt; 0.0001), internal validation set (P = 0.0039) and external validation set (P = 0.04). Moreover, in patients treated with RCHOP-like therapy, the ICPI was also predictive (P &lt; 0.0001). In comparison to FLIPI, FLIPI2, and PRIMA-PI (C-index, 0.613-0.647), the ICPI offered adequate discrimination capability with C-index values of 0.679. Additionally, it exhibits good performance based on the lowest AIC and highest likelihood ratio chi-square score.ConclusionsThe ICPI is a novel predictive model with improved prognostic performance for patients with de novo FL treated with R-CHOP/CHOP chemotherapy. It is capable to be used in routine practice and guides individualized precision therapy.