LOXL2 Highly-Expressed Induce the Transition of Stromal Cells into Cancer-Associated Fibroblasts Which Maybe Involve in Myeloproliferative Neoplasms Progession

Backgroud and objective: Myeloproliferative neoplasms (MPNs) are malignant disorders by proliferation of one of the myeloid lineages and characteristically show an increase in bone marrow reticulin reticulin-fibrosis.Lysyl oxidases like-2(LOXL2) is copper-dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin,and Cancer associated-fibroblasts (CAFs) are major mediators in tumor microenvironment. Studies found that loxl2 stimulate CAFs grouth solid tumor,and the expression of LOXL2 is increased in MPN patients,espessionly in PMF patients.Here, we want to evaluate whether the expression of higher LOXL2 associated to CAFs during various MPN progression.

Patients and methods: We compared normal bone marrows and those from patients with chronic myeloid leukemia(CML)(include CML-CP n=20,CML-BC n=13),polycythemia vera(PV)(n=18), essential thrombocythemia(ET) (n=23), and primary myelofibrosis (PMF) (n=8). We detected α-smooth actin and reticulin protein by immunohistochemical staining, examined LOXL2 expression by western blot in bone marrow and ELIZA kit in serum.

Results: LOXL2 was not detected in normal bone marrows and serum.The level of LOXL2 gene is over expressed in PMF (p<0.01) and CML-BC (p=0.02). In other MPNs a differential pattern of expression were statistically significant (P< 0.010).The level of LOXL2 expression associated with reticulin protein expression in bone marrow, especially if reticulin protein expressed higher than 2+(p=0.01).

We detected α-smooth actin positive stromal cells in CML-BC and PMF patients,and the level of LOXL2 expression is related to α-smooth actin positive stromal cells(p<0.05).we also detected α-smooth actin after co-cultured mesenchymal stem cell(MSCs) with sLOXL2 for 96 hour.

Conclusion: Higher level of LOXL2 could be promote MPN progression by modulating several functions of surrounding stromal cells which acquire features of cancer-associated fibroblasts involved in the pathogenesis of MPN. These findings maybe used as the basis for future targeted therapy directed against MPN progression.