TGF-β1 induces bone marrow reticulin fibrosis in hairy cell leukemia

Abstract

Nonstandard abbreviations used: B cell chronic lymphocytic leukemia (B-CLL); bone marrow (BM); BM fibroblast (BMF); BM mononuclear cell (BMMC); BM plasma (BMP); BM stromal cell (BMSC); hairy cell (HC); HC leukemia (HCL); healthy donor (HD); peripheral blood plasma (PBP); procollagen type III aminoterminal propeptide (PIIINP). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionHairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by the presence of hairy cells (HCs) in peripheral blood, bone marrow (BM), and spleen and is invariably associated with a unique type of BM fibrosis (1-3). Although a rare disease (2% of adult leukemia), HCL represents an excellent model for cancer biotherapy (4) and for understanding the deregulation of cytokines and growth factors in human neoplasia (5-7). The fibrotic process and the associated structural abnormality in BM of HCL patients are mainly due to accumulation of fine argyrophilic reticulin fibers, although collagen fibers can be observed in the advanced stages of the disease (8-11). The composition of reticulin fibers in HCL is not well defined. In normal and fibrotic BM, the distribution of reticulin fibers is identical to that of type III collagen and its precursor, type III procollagen (12,13). Electron microscopic studies of human tissues revealed that reticulin fibers are individual collagen fibrils or small bundles of these fibrils embedded in the interfibrillar matrix of proteoglycans (14-16) and that they are composed mainly of type III collagen surrounding a core of type I collagen fibrils (17,18). In addition to reticulin fibrosis, it has been recently demonstrated that the glycoprotein fibronectin, which is produced and assembled by HCs, contributes to the fibrotic process in BM of HCL patients (19). This process was also found to be particularly enhanced by bFGF, which is endogenously produced by the HCs (20). Since reticulin and fibronectin fibers were found to represent different structures in myelofibrotic BM (21), it appears that BM fibrosis in HCL is a complex process that involves accumulation and assembly of collagenous ECM components (reticulin) (22) and noncollagenous ECM components (fibronectin).In BM, HCs are found in association with randomly dispersed fibroblastoid cells and are surrounded by reticulin fibers (9, 10, 23, 24). These fibroblastoid cells, which have been found in close association with collagen fibers, are the matrix-producing cells and are responsible for the synthesis of reticulin and collagen (9,(25)(26)(27)(28). Other studies confirmed the increase in the collagen fibrils in the intercellular space around the HCs but did not find evidence that HCs give rise to these fibrils (10). These studies also showed that HCs are not argyrophilic (29), suggesting that they may not be the direct source of reticulin fibers. Since no massive increase in fibroblast numbers is observed in the BM of HCL patients (10), the increased production of reticulin and ECM proteins mig...

Nsa2 Is an Unstable, Conserved Factor Required for the Maturation of 27 SB Pre-rRNAs

“…These authors suggest that TINP1, together with two other noncharacterized genes found in this region, constitute a candidate tumor suppressor gene (21). Moreover, recent evidence suggests that high levels of transforming growth factor-␤ are secreted by hairy cells and favor the progression of the pathology (22). An appealing hypothesis would therefore be that deregulation of TINP1 expression could participate in the progression of the disease either because of chromosomal abnormalities or because of stimulation by transforming growth factor-␤.…”

TGF-β signaling in the control of hematopoietic stem cells

“…These include TGF-b, fibroblast growth factor 2 (FGF-2), and platelet-derived growth factor. [109][110][111][112] Some of the most compelling evidence for a prominent role of TGF-b in myelofibrosis comes from a study using Tgfb1-null mice. To induce myelofibrosis, irradiated mice were transplanted with BM cells transduced with vectors containing the thrombopoietin gene.…”

The role of Smad signaling in hematopoiesis and translational hematology

“…These include TGF-b, mainly TGF-b1, basic fibroblast growth factor and platelet-derived growth factor. [105][106][107][108] Some of the strongest evidence for a prominent role of TGF-b in the generation of myelofibrosis involved the use of BM cells from Tgf-b1 null mice. To induce myelofibrosis, irradiated mice were transplanted with BM cells transduced with vectors containing the thrombopoietin gene.…”