Plasma cells arise from differentiation of clonal lymphocytes and secrete IgM in Waldenström macroglobulinemia

Jun Hee Lim; James Q Wang; Fiona Webb; Kartik Saxena; Daniel Enosi Tuipulotu; Abhimanu Pandey; Si Ming Man; Dipti Talaulikar

doi:10.1016/j.isci.2022.104856

Plasma cells arise from differentiation of clonal lymphocytes and secrete IgM in Waldenström macroglobulinemia

iScience. 2022 Aug 4;25(8):104856. doi: 10.1016/j.isci.2022.104856. eCollection 2022 Aug 19.

Authors

Jun Hee Lim^{1

2

3}, James Q Wang⁴, Fiona Webb⁵, Kartik Saxena¹, Daniel Enosi Tuipulotu³, Abhimanu Pandey³, Si Ming Man³, Dipti Talaulikar^{1

2

3}

Affiliations

¹ Haematology Translational Research Unit, Canberra Hospital, Canberra, Australia.
² ANU Medical School, College of Medicine and Health, Australian National University, Canberra, Australia.
³ Division of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
⁴ ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
⁵ Department of Diagnostic Genomics, ACT Pathology, Canberra, Australia.

Abstract

Waldenström macroglobulinemia (WM) is characterized by bone marrow infiltration with malignant lymphoplasmacytic cells (LPCs), a smaller population of plasma cells (PCs), and hypersecretion of IgM monoclonal protein. Here, we show that CD45^low, CD38⁺, and CD138⁺ PCs and CD45^high, CD38^-, CD138^-, CD19⁺, and CD20⁺ LPCs carry a heterozygous L265P mutation in the Toll-like receptor signaling adaptor MYD88. Both PCs and LPCs express the same auto-reactive IgHV sequences, suggesting a similar clonal origin and role for auto-antigens in WM cell survival. PCs are primarily responsible for IgM production even without substantial cell proliferation. When cultured in isolation, LPCs give rise to more differentiated PCs and secrete less IgM. Our analyses suggest that malignant PCs arise from the clonal LPC population, and are primarily responsible for IgM secretion in WM. Targeting malignant PCs may have therapeutic benefits in the treatment of WM and improve the duration of response and potentially, survival.

Keywords: Cancer; Cell biology; Immune system disorder; Immunology.