Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection - PubMed (original) (raw)

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Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection

Nikolaos Papadantonakis et al. Blood. 2012.

Abstract

Megakaryocytes (MKs), the platelet precursors, are capable of accumulating DNA greater than a diploid content as part of their cell cycle. MKs have been recognized as mediating fibrosis in a subset of hematologic malignancies, including acute megakaryoblastic leukemia and a subset of myeloproliferative neoplasms. The mechanisms responsible for fibrosis remain only partially understood. Past studies highlighted the role of growth factors in such pathologies, and recently, the protein lysyl oxidase (LOX) has been implicated in proliferation of MKs, ploidy and deposition of fibers. LOX was initially characterized as a protein responsible for the intermolecular cross-linking of elastin and collagen, and in recent years it has been identified as regulator of various pathologies, such as cancer and inflammation. Here, we review recent advances in the understanding of the contribution of MKs to the progression of myelofibrosis, highlighting the newly identified role of LOX.

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Figures

Figure 1

Figure 1

Effect of LOX inhibition on marrow fibrosis in vivo. (A) Representative hematoxylin and eosin (left column) and Gomori silver (right column) staining of longitudinal sections of femurs from wild-type and GATA-1low (male littermates), control, or BAPN-treated mice (10.5 weeks old at the time of collection). Original magnifications: left column, ×400; and right column, ×600. Arrows indicate the large presence of MKs (hematoxylin and eosin stain) and the accumulation of reticulin fibers in the GATA-1low mice. Images obtained using Nikon Eclipse 50i microscope equipped with a 40× Plan (numerical aperture 0.65) and a 60× Plan Fluor (numerical aperture 0.85) objectives. Digital images acquired using a SPOT 2 megapixel camera and SPOT 5.0 acquisition software. (B) Quantification of fibrosis in BAPN or vehicle-treated GATA-1low mice. Fibers were measured in arbitrary units from stained sections. Data are represented as absolute values (top panel) or as mean percent change compared with values recorded from vehicle-treated GATA-1low mice (bottom panel). The mean values were obtained from 5 mice per group. **P < .05. Reproduced from Eliades et al75 with permission.

Figure 2

Figure 2

Possible mechanisms of contribution of LOX to progression of myelofibrosis. Low-ploidy MKs have elevated levels of expression of LOX, which is secreted to the BM microenvironment. The active LOX enzyme promotes cross-linking of matrix collagen and consequent fiber deposition. The active LOX enzyme also oxidizes the PDGF receptor, enhancing the proliferative response from this receptor. Inhibition of LOX by BAPN may reverse this process. High-ploidy MKs express very low amounts of LOX.

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References

    1. Ravid K, Lu J, Zimmet JM, Jones MR. Roads to polyploidy: the megakaryocyte example. J Cell Physiol. 2002;190(1):7–20. - PubMed
    1. Geddis AE. Megakaryopoiesis. Semin Hematol. 2010;47(3):212–219. - PMC - PubMed
    1. Lion T, Haas OA. Acute megakaryocytic leukemia with the t(1;22)(p13;q13). Leuk Lymphoma. 1993;11(1):15–20. - PubMed
    1. Shimizu R, Engel JD, Yamamoto M. GATA1-related leukaemias. Nat Rev Cancer. 2008;8(4):279–287. - PubMed
    1. Crispino JD. GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol. 2005;16(1):137–147. - PubMed

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