B‐cell signaling in persistent polyclonal B lymphocytosis (PPBL)

Abstract

Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)-like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF-κB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF-κB signaling after CD40 stimulation and both B-cell receptor- and Toll-like receptor 9-mediated activation remained unaffected. Reduced canonical NF-κB activation resulted in decreased IκBα and CD40 expression in resting cells. In PPBL patients, expression of Bcl-xL in MZ-like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL-derived B cells that were observed in vitro. The B-cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ-like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF-κB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL.

Absence of driver mutations in persistent polyclonal B-cell lymphocytosis with binucleated lymphocytes

“…Interestingly, another study of 4 patients failed to identify exonic mutations in a panel of 12 nuclear factor kappa B pathway genes. 12 We conclude that PPBL is not driven by protein-coding mutations. However, we cannot exclude a role for mutations outside coding sequences or modifications of the epigenetic state, but these hypothesis were not evaluated in this study.…”

Postmenopausal Uterine Leiomyomas and Chronic Lymphadenopathy: Exploring Epigenetic Changes and Pathophysiology

“…Instead, in the literature, polyclonal B cell lymphadenopathy is most consistent with a benign disease called persistent polyclonal B-cell lymphocytosis, an indolent stable disease characterized by the presence of abundant binucleated lymphocytes in the marginal zone of the lymph node [18]. Defects in early cell signaling components such as in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) have been implicated as a potential mechanism for this polyclonal proliferation [19]. These alterations in lymphocyte replication may be unrelated to the epigenetic modifications involved in the pathogenesis of LM as the correlation between these two phenomena have yet to be established.…”

Loss of the Fanconi anemia–associated protein NIPA causes bone marrow failure

“…Chromosomes were stained with DAPI (1.0 × 10 -6 g/mL in PBS buffer, pH 7.0), mounted with antifade (Vector Laboratories), and scaled with a coverslip. Digital images were recorded with a digital camera (Sensys, Photometrics) on an Axioplan II fluorescence microscope (Zeiss) with Plan Apochromat 63/40 or 100/1.30 objectives (room temperature) using the Vysis workstation QUIPS (76).…”