S100A16 suppresses the growth and survival of leukaemia cellsand correlates with relapse and relapse free survival in adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia

摘要

Refinement of risk stratification in Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukaemia (ALL) might aid the identification of patients who are likely to relapse. Abnormal S100 calcium binding protein A16 (S100A16) has been implicated in various cancers, but its function remains unclear. We found S100A16 transcript levels were higher in 130 adults with newly-diagnosed Ph-negative B-cell ALL compared with 33 healthy controls. In 115 of 130 patients who achieved first complete remission, those with high S100A16 transcript levels displayed a lower 3-year cumulative incidence of relapse (CIR; 34% [21, 47%] vs. 40% [48, 72%]; P=0012) and higher 3-year relapse-free survival (RFS; 65% [53, 78%] vs. 35% [23, 46%]; P=0012), especially when receiving chemotherapy only. In multivariate analysis a low S100A16 transcript level was independently-associated with a higher CIR (Hazard ratio [HR]=374 [101-1382]; P=0048) and inferior RFS (HR=578 [191, 1784]; P<0001). Function analysis indicated that knockdown of S100A16 promoted proliferation and anti-apoptosis and reduced chemosensitivity. S100A16 over-expression revealed an opposite trend, especially in a xeno-transplant mouse model. Western blotting analysis showed upregulation of PI3K/AKT and ERK1/2 in S100A16-knockdown and S100A16-overexpression B-cell ALL cell lines respectively. Inhibition assays suggested these two signalling pathways participated in the S100A16-mediated proliferation and survival effects in B-cell ALL cell lines.