PIM1 genetic alterations associated with distinct molecular profiles, phenotypes and drug responses in diffuse large B‐cell lymphoma

Abstract

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.

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family

“…6C). Interestingly, CARD10 R212 aligns with R207 in CARD11—and the CARD11 R207H mutation has been picked up in genetic B cell lymphoma screenings [82,83]—which supports that this mutation is likely to be activating. In comparison to the extremely rare activated CARD9 G111E allele is CARD10 R212H far more common, with 25 cases out of 394 841 being reported in the Genebass database.…”

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

“…4c). Interestingly, CARD10 R212 aligns with R207 in CARD11 — and the CARD11 R207H mutation has been picked up in genetic B cell lymphoma screenings [66], [67] — which supports that this mutation is likely to be activating. In comparison to the extremely rare activated CARD9 G111E allele, CARD10 R212H is far more common, with 25 cases out of 394841 being reported in the Genebass database.…”

Circulating Tumor DNA Reflects Histologic and Clinical Characteristics of Various Lymphoma Subtypes

“…There were frequent in the PIM1 , BCL2 , and KMT2D genes in the plasma samples from patients with DLBCL and FL in this study. The PIM1 mutation is not only thought to be involved in the pathogenesis of DLBCL [ 26 ], but also related to ibrutinib resistance in DLBCL [ 27 ]. We identified 17 nonsynonymous mutations in seven DLBCL patients and one FL patient with VAF ranging 1.9% to 20.3%.…”