Normal B cells express ZAP70 in chronic lymphocytic leukemia: A link between autoimmunity and lymphoproliferation?

Abstract

ZAP70 has a prognostic value in chronic lymphocytic leukemia (CLL), through altered B-cell receptor signaling, which is important in CLL pathogenesis. A good correlation between ZAP70 expression in CLL cells and the occurrence of autoimmune phenomena has been reported. Yet, the great majority of CLL-associated autoimmune cytopenia is due to polyclonal immunoglobulin (Ig) G synthesized by nonmalignant B cells, and this phenomenon is poorly understood. Here, we show, using flow cytometry, that a substantial percentage of CD5- nonmalignant B cells from CLL patients expresses ZAP70 compared with CD5- B cells from healthy subjects. This ZAP70 expression in normal B cells from CLL patients was also evidenced by the detection of ZAP70 mRNA at single-cell level with polyclonal Ig heavy- and light-chain gene transcripts. ZAP70+ normal B cells belong to various B-cell subsets and their presence in the naïve B-cell subset suggests that ZAP70 expression may occur during early B-cell development in CLL patients and potentially before malignant transformation. The presence of ZAP70+ normal B cells is associated with autoimmune cytopenia in CLL patients in our cohort of patients, and recombinant antibodies produced from these ZAP70+ nonmalignant B cells were frequently autoreactive including anti-platelet reactivity. These results provide a better understanding of the implication of ZAP70 in CLL leukemogenesis and the mechanisms of autoimmune complications of CLL.

• Authors: Dana Ghergus, Mickaël Martin, Anne-Marie Knapp, Fabien Delmotte, Aurélie Joublin-Delavat, Sophie Jung, Jean-Nicolas Schickel, Isabelle Mendel, Arnaud Dupuis, Bernard Drénou, Hervé Ghesquières, Gilles Salles, Lucile Baseggio, Raoul Herbrecht, Anne-Sophie Korganow, Laurent Vallat, Pauline Soulas-Sprauel, Eric Meffre, Thierry Martin
• Journal: American journal of hematology (Am J Hematol) Vol. 99 Issue 1 Pg. 48-56 (Jan 2024) ISSN: 1096-8652 [Electronic] United States
• PMID: 37853951 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.

Chemical References

• ZAP70 protein, human
• ZAP-70 Protein-Tyrosine Kinase

Topics

• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell
• Autoimmunity
• B-Lymphocytes
• Flow Cytometry
• Prognosis
• ZAP-70 Protein-Tyrosine Kinase (genetics, metabolism)