The expression of lysyl‐oxidase gene family members in myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are malignant disorders originating from clonal expansion of a single neoplastic stem cell and characteristically show an increase in bone marrow reticulin fibers. Lysyl oxidases (LOXs) are copper‐dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin. Expression of LOX gene family members is increased in disorders associated with increased fibrosis. To evaluate involvement of LOX gene family in various MPNs. In‐situ hybridization was used to detect Lysyl‐Oxidase family members in bone marrow biopsies from patients with different MPNs. We compared normal bone marrows and those from patients with polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, and primary myelofibrosis (PMF). Serum levels of lysyl‐oxidase from patients with PMF and healthy controls were also examined. LOX gene family was not detected in normal bone marrows. All members of the LOX gene family were over expressed in PMF. In other MPNs a differential pattern of expression was observed. Differences in gene expression were statistically significant (P < 0.010). The medianserum LOX levels in normal controls was 28.4 ± 2.5 ng\ml and 44.6 ± 9.44 ng\ml in PMF (P = 0.02). The varying pattern of expression of LOX genes may reflect differences in the pathophysiology of bone marrow fibrosis in these MPNs. These observations could be used as the basis for future targeted therapy directed against bone marrow fibrosis. Am. J. Hematol. 88:355–358, 2013. © 2013 Wiley Periodicals, Inc.

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

“…2 Analyses of MPN patient samples corroborated our findings, reporting elevated levels of LOX in sera and megakaryocytes as compared with matching control samples. 4 In analyzing published gene profiling arrays, 44 we noted LOX as upregulated by 2.6-to 2.9-fold in human primary myelofibrosis samples compared with normal samples, depending on the LOX probes used in the microarrays. MPNs are associated with a tendency for activated platelets and thrombosis, the mechanisms of which have remained elusive.…”

“…2,4 To test the direct effect of LOX on platelet function, free of compounding influences of MPNs, we generated Pf4-Lox tg/tg mice in which LOX protein is expressed on a WT background, driven by the megakaryocyte lineage-specific Pf4 gene promoter, as described in numerous other studies. 29,30 LOX protein expression was detected in purified megakaryocytes from Pf4-Lox tg/tg mice, but not in WT control BSA-purified megakaryocytes ( Figure 1A).…”

“…3 Two reports have since corroborated our findings by demonstrating higher levels of LOX in the bone marrow and sera of patients with MPNs and other types of fibrosis. 4,5 Philadelphia chromosome-negative MPNs 6 are a group of disorders characterized by proliferation of dysmorphic megakaryocytes and myelofibrosis in the bone marrow. In 1951, William Dameshek proposed that polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis share a common pathogenesis, based on similarities observed in clinical and bone marrow morphologic findings.…”

Emerging treatments for classical myeloproliferative neoplasms

“…LOX levels have been found elevated in patients with MF. 119 In GATA-1 low mice, LOX inhibition led to decrease of bone marrow fibrosis. 120 Simtuzumab, a humanized antibody against LOXL2, was used in 54 patients with MF; treatment was well tolerated, but no clear signal of response was observed.…”

Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies

“…Furthermore, serum LOX levels were significantly higher in PMF patients than in a control group. 93 Simtuzumab is a humanized monoclonal antibody that binds to and inhibits LOXL2. A phase II trial of simtuzumab monotherapy (stage 1) and combination therapy with ruxolitinib (stage 2) in patients with intermediate-1 or higher risk MF has completed recruitment and the results were recently presented (NCT01369498).…”