https://orcid.org/0000-0001-8614-4782
Key Points
Patients with AL amyloidosis show changes in malignant plasma cell (PC) and enrichment in a newly defined, normal PC subset.
An inflammatory transcriptional signature characterizes the bone marrow microenvironment in AL amyloidosis.
Subjects:
Lymphoid Neoplasia
Abstract
AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5’ single-cell RNA sequencing on newly diagnosed, treatment-naïve patients with AL amyloidosis and healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of monocytes and subsets of CD4+ T cells in patients with AL amyloidosis. We detected significant transcriptional changes broadly occurring among immune cells with increased tumor necrosis factor-α signaling and interferon response accompanied by increased inflammatory response in bone marrow plasma, as measured via quantitative proteomics with specific elevation of costimulatory molecule soluble CD276 (sB7-H3). A transcriptionally distinct population of nonmalignant plasma cells was disproportionately expanded in patients with AL amyloidosis and characterized by increased expression of CRIP1. Finally, clonal AL amyloidosis plasma cells were identified based on their unique variable-diversity-joining. rearrangement and showed increased expression of genes involved in proteostasis when compared with autologous, polyclonal plasma cells. Interpatient transcriptional heterogeneity was evident, with transcriptional states reflective of common genomic translocations easily identifiable. This study defines the transcriptional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment with identification of altered genes previously involved in the pathogenesis of other protein deposition disorders. Our data provide the rationale for functional validations of these genes in future studies.
Subjects:
Lymphoid Neoplasia
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Comments
From fibrils to inflammation and fibrosis: a conserved tissue response in AL
Jordan et al. previously demonstrated that AL fibrils trigger inflammatory gene upregulation in cardiomyocytes and mesenchymal stromal cells[2]. Similarly, we have observed inflammatory pathway upregulation, including TNF-α, interferon, and toll-like receptor signaling, in advanced renal AL amyloidosis (unpublished), suggesting a conserved cellular response.
The study's identification of extracellular matrix (ECM) remodeling pathways is equally noteworthy. We have observed analogous features,that is ECM dysregulation and epithelial-to-mesenchymal transition (EMT) [3] , in proteomic analyses of both AL and ATTR cardiac tissues [4]and advanced renal AL (unpublished). Critically, myocardial fibrosis volume matches amyloid deposits but localizes separately, independently impairing cardiac function [5].
These observations suggest two critical insights. First, targeting common inflammatory and fibrotic pathways may benefit multiple amyloidoses beyond clone-directed therapy. However, this fibrotic response may limit organ recovery even after successful amyloid clearance, emphasizing the imperative for early intervention before irreversible tissue remodeling occurs.
Taxiarchis Kourelis, Angela Dispenzieri, Surendra Dasari, Shaji Kumar.
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
1.Gort-Freitas, N.A., et al., Single-cell and clonal analysis of AL amyloidosis plasma cells and their bone marrow microenvironment. Blood, 2025. 146(12): p. 1476-1492.
2.Jordan, T.L., et al., Light chain amyloidosis induced inflammatory changes in cardiomyocytes and adipose-derived mesenchymal stromal cells. Leukemia, 2020. 34(5): p. 1383-1393.
3.Youssef, K.K. and M.A. Nieto, Epithelial-mesenchymal transition in tissue repair and degeneration. Nat Rev Mol Cell Biol, 2024. 25(9): p. 720-739.
4.Netzel, B.C., et al., Whole tissue proteomic analyses of cardiac ATTR and AL unveil mechanisms of tissue damage. Amyloid, 2025. 32(1): p. 72-80.
5.Pucci, A., et al., Amyloid Deposits and Fibrosis on Left Ventricular Endomyocardial Biopsy Correlate With Extracellular Volume in Cardiac Amyloidosis. J Am Heart Assoc, 2021.10(20): p.e020358