Abstract
Abstract Large Granular Lymphocyte (LGL) leukemia is associated with unexplained cytopenias, autoimmune features, and CD57+CD8+perforin+ T-cell lympoproliferation. Like many autoimmune disorders, the pathophysiology of cytopenias in LGL leukemia is unknown. Bone marrow (BM) pathology from 24 LGL leukemia patients was retrospectively studied using H&E, reticulin, and trichrome-stained sections, and revealed that BM fibrosis was present in 21 out of 24 patients (88%). Fibrosis, a previously undefined complication, was significantly associated with splenomegaly, the presence of cytopenias, and coexistance of autoimmune diseases. LGL cell numbers in the BM, but not peripheral blood, was associated with fibrosis severity. Colony forming assays in the presence of exogenous bioartificial collagen matrix using healthy bone marrow mononuclear cells (BM-MNCs) revealed a direct inhibitory effect of collagen on progenitor growth. Consistent with microarray analysis, primary mesenchymal stromal cultures (MSCs) from LGL leukemia BM displayed heightened collagen deposition. In co-culture assays, collagen matrix produced by LGL MSCs directly inhibited healthy hematopoietic progenitor growth support. This study demonstrates that excessive collagen matrix deposition by deregulated MSCs may result from the local BM accumulation of activated CD8+ LGL leukemia T-cells. Therefore, BM fibrosis should be explored as a mechanism for secondary cytopenias associated with autoimmune diseases.
Published Version
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