Long non-coding RNA LINC00926 is a biomarker for naïve B-cells with prognostic value in advanced stage classic Hodgkin lymphoma - LETTER TO THE EDITOR

Q: Why is naïve B-cell content considered clinically relevant in classic Hodgkin lymphoma?

Naïve B-cell content in the tumor microenvironment has been associated with favorable outcome, supported by analyses of bulk tissue gene expression and whole slide images.

Q: What made LINC00926 a candidate biomarker for naïve B-cells?

LINC00926 expression patterns were restricted to the B-cell lineage in peripheral blood mononuclear cell datasets and were strongly downregulated following B-cell activation.

Q: How was LINC00926 evaluated in Hodgkin lymphoma biopsies?

A NanoString custom panel including LINC00926 was applied to 23 specimens from the NIVHAL trial, showing strong correlation with B-cell marker genes and with naïve B-cell content scores assessed using CIBERSORTx.

Sep 29, 2026

Uploaded by Levi

Letter to the editor describing evidence that the long non-coding RNA LINC00926 functions as a biomarker for naïve B-cells and may carry prognostic relevance in advanced stage classic Hodgkin lymphoma. Data from gene expression profiling, whole-slide image analysis, and single-cell RNA sequencing support a link between naïve B-cell content and favorable outcomes, while LINC00926 is shown to be selectively downregulated after B-cell activation. NanoString analysis of NIVHAL trial specimens and correlation with established B-cell markers further supports LINC00926’s specificity and potential clinical utility.

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LETTER TO THE EDITOR

Background and rationale

Identification of LINC00926

Validation in Hodgkin lymphoma tissue

Single-cell RNA-seq confirmation

LETTER TO THE EDITOR Long non-coding RNA LINC00926 is a biomarker for naïve B-cells with prognostic value in advanced stage classic Hodgkin lymphoma In classic Hodgkin lymphoma (HL), neoplastic Hodgkin and Reed-Sternberg cells (HRSC) account for less than 5% of the tumor mass. The remaining 95% of the tumor is composed of various cell types of the immune system. Among the tumor infiltrating lymphocytes, a high B-cell content in the tumor microenvironment (TME) of HL has been associated with favorable outcome. This phenomenon was demonstrated by gene expression profiling of the bulk tissue as well as whole slide image analysis.1-3 Given the clinical relevance of B-cell content in HL, we and others have studied the composition of B-cell subtypes in the TME of HL patients and found that the number of naïve B cells correlates with B-cell content.3,4 Recently, single-cell RNA sequencing (scRNA-Seq) showed that up to 30% of the cells in HL TME belong to B-cell clusters, with 70% of these cells being defined as naïve B cells.5,6 The data also show that HL TME contains ten times less germinal center (GC) derived B cells relative to a reactive lymph node.6 It is, therefore, reasonable to speculate that the prognostic value of B-cell content is associated with content of naïve B cells, more than with other B-cell subtypes. Evaluation of tissue infiltrating naïve B cells requires detection of multiple surface markers,4 which can be technically challenging. A single biomarker specific for infiltrating naïve B cells is not yet available. Given that the expression of long non-coding RNA (lncRNA) is known to be highly cell type specific relative to protein coding genes,7 we sought to identify lncRNA transcripts that could be used as markers for the detection of naïve B cells in tissue sections. A similar analysis of lncRNA expression in normal B-cell subsets and in HL cell lines has been previously performed for the identification of HL-specific lncRNA transcripts.8 First, we explored publicly available gene expression data sets to search for B-cell specific transcripts.9,10 The lncRNA LINC00926 was selected for further analysis due to its expression pattern in purified subsets of peripheral blood mononuclear cells (PBMC) that was restricted to the B-cell lineage, similar to the B-cell marker CD20 (Figure 1A, B) . To confirm an expression pattern limited to B cells, we also interrogated other expression datasets available at the Genotype-Tissue Expression (GTEx) Portal, the Expression Atlas of the European Molecular Biology Labora- A B C D Figure 1. The lncRNA LINC00926 is specifically expressed in resting naïve B cells. RNA-Seq data from Calderon et al.9 was analyzed for the expression of the CD20 gene (MS4A1) and the lncRNA LINC00926 in different peripheral blood mononuclear cells (PBMC) cellular components (A and B) and in naïve and memory B cells under resting condition or after stimulation with anti-IgG/ IgM + IL-4 (C and D) . The difference in expression between naïve resting and memory resting B cells, as well as between naïve resting and naïve stimulated B cells, was significant for LINC00926 (**P<0.05) and not significant (n.s.) for MS4A1 . NK: natural killer cells; TPM: transcripts per million; Tregs: regulatory T cells. Haematologica | 111 January 2026 LETTER TO THE EDITOR tory’s European Bioinformatics Institute and the Cancer Cell Line Encyclopedia of the Broad Institute. Data from all these databases confirmed that LINC00926 expression is restricted either to the blood or to lymphocyte rich organs (spleen, small intestine) or to cancer cells with B lymphocytic origin. Interestingly, in the Calderon dataset,9 the transcript LINC00926 was strongly down-regulated following B-cell activation in both naïve and memory B cells (Figure 1D) . In the same dataset, expression of CD20 was not differentially expressed comparing either naïve and memory B cells or stimulated and unstimulated cells (Figure 1C) . These data in

FAQs

Why is naïve B-cell content considered clinically relevant in classic Hodgkin lymphoma?

Naïve B-cell content in the tumor microenvironment has been associated with favorable outcome, supported by analyses of bulk tissue gene expression and whole slide images.

What made LINC00926 a candidate biomarker for naïve B-cells?

LINC00926 expression patterns were restricted to the B-cell lineage in peripheral blood mononuclear cell datasets and were strongly downregulated following B-cell activation.

How was LINC00926 evaluated in Hodgkin lymphoma biopsies?

A NanoString custom panel including LINC00926 was applied to 23 specimens from the NIVHAL trial, showing strong correlation with B-cell marker genes and with naïve B-cell content scores assessed using CIBERSORTx.

Sep 29, 2026

Uploaded by Levi