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Malignant B cells expressing SIRPα are highly proliferative and are associated with inferior clinical outcomes in B-cell non-Hodgkin lymphoma

Leukemia (2026)Cite this article

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Signal regulatory protein alpha (SIRPα), a transmembrane glycoprotein, plays a pivotal role in regulating immune responses, particularly in monocytes and macrophages [1]. Its expression is tightly regulated, with levels modulated by various factors, including cytokines [2]. Functionally, SIRPα acts as a receptor for CD47, a widely expressed marker of self, thereby mediating immune checkpoint signaling [3] and regulating phagocytosis [4]. Furthermore, aberrant expression and dysregulation of SIRPα have been implicated in various cancers, where its interaction with CD47 facilitates immune evasion and tumor progression by inhibiting phagocytosis of cancer cells [5]. Thus, targeting the SIRPα-CD47 axis has emerged as a promising immunotherapeutic strategy for enhancing anti-tumor immune responses and overcoming immune evasion mechanisms in cancer therapy [6, 7].

Gaining SIRPa expression may result in a phenotypical change in B cells and also in distinct transcriptomic and proteomic profiles. We observed that SIRPα+ B cells differed from SIRPα- cells as the multidimensional scaling (MDS) analysis exhibited a substantial dissimilarity (distance) between these two subsets in FL and sMZL (Fig. S3A). Gene profiling analysis revealed that many genes were differentially expressed between SIRPα+ and SIRPα- B cells (Fig. 1F). Using CD38 and IgD to define B subsets, we found that SIRPα+ B cells were mainly seen in the memory (MBC) and germinal center (GC) B cell compartment (Fig. 1G). MBC, especially those that had not undergone class switching (nSwitched), and naïve B (NBC) cells expressed higher and lower levels of SIRPα, respectively (Fig. 1H), which was supported by increased expression of CD27, a memory marker, on SIRPα+ B cells when compared to SIRPα- B cells (Fig. S3B). By freshly isolating naïve and memory B cells, we further confirmed that SIRPα was more abundantly expressed on memory than naïve B cells (Fig. S3C). To address whether SIRPα is preferentially expressed on malignant or non-malignant B cells in lymphoma biopsies, we utilized cellular clonality (immunoglobulin light chain dominance) to distinguish malignant from non-malignant B cells. As shown in Fig. S3D, SIRPα expression at both the RNA and protein level was predominantly expressed on Ig light chain-restricted B cells in 3 of 4 patients in whom clonality could be reliably determined, suggesting that SIRPα is preferentially expressed on malignant B cells.

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Fig. 1: Lymphoma B cells express SIRPα that exhibit distinct transcriptomic and proteomic profiles compared to SIRPα- B cells.
Fig. 2: SIRPα+ B cells are more proliferative and correlate with inferior patient outcomes in FL.

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Acknowledgements

Supported in part by grants from the National Institutes of Health (P50 CA97274), the Institute for Follicular Lymphoma Innovation, the Lymphoma Research Foundation, the Department of Defense (W81XWH1810650), and the Predolin Foundation.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Zhi-Zhang Yang, Hyo Jin Kim, Xinyi Tang, Joseph P. Novak, Vaishali Bhardwaj, Prithviraj Mukherjee, Jose C. Villasboas, Anne J. Novak, Patrizia Mondello & Stephen M. Ansell

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  1. Zhi-Zhang Yang
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Contributions

ZZY and SMA designed the research, analyzed data and wrote the paper; ZZY, HJK, XT, JPN, JCV, VB, and PM performed experiments and analyzed data; AJN and PMondello wrote the paper. All authors reviewed and approved the final manuscript.

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Correspondence to Zhi-Zhang Yang or Stephen M. Ansell.

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The authors declare no competing interests.

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All methods were performed in accordance with relevant guidelines and regulations. Patients providing written informed consent were eligible for this study if they had a tissue biopsy that on pathologic review showed FL and adequate tissue to perform the experiments. The use of human tissue samples for this study was approved by the Institutional Review Board of the Mayo Clinic/Mayo Foundation. No identifiable images from human research participants are included in this publication

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Yang, ZZ., Kim, H.J., Tang, X. et al. Malignant B cells expressing SIRPα are highly proliferative and are associated with inferior clinical outcomes in B-cell non-Hodgkin lymphoma. Leukemia (2026). https://doi.org/10.1038/s41375-026-02872-y

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