S100A16suppresses the growth and survival of leukaemia cells and correlates with relapse and relapse free survival in adults with Philadelphia chromosome‐negative B‐cell acute lymphoblastic leukaemia

Abstract

Summary 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 = 0·012) and higher 3‐year relapse‐free survival (RFS; 65% [53, 78%] vs. 35% [23, 46%]; P = 0·012), especially when receiving chemotherapy only. In multivariate analysis a low S100A16 transcript level was independently‐associated with a higher CIR (Hazard ratio [HR] = 3·74 [1·01–13·82]; P = 0·048) and inferior RFS (HR = 5·78 [1·91, 17·84]; P < 0·001). 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. Trial Registration: Registered in the Chinese Clinical Trial Registry [ChiCTR‐OCH‐10000940]; http://www.chictr.org.cn.

Prognostic value of RASD1 transcript levels in adult Philadelphia-negative B-cell acute lymphoblastic leukemia

“…The definition of overexpression is the basis for analysing the clinical significance of RASD1 in Ph-negative B-ALL. In this study we used the median transcript level of RASD1 in Ph-negative B-ALL patients to divide the patients into a high expression group and a low expression group as reported [20,27]. We found that a low RASD1 transcript level at diagnosis was associated with a higher risk of relapse in patients with Phnegative B-ALL, especially in patients receiving chemotherapy only.…”

“…However, this correlation should be interpreted with caution, because it may be partially due to the relatively small number of cases in the allo-HSCT group. In addition, many factors may affect the outcome of allo-HSCT, such as donor-recipient gender matching, HLA disparity, and monitoring and intervention for MRD [20]. An analysis combining RASD1 transcript levels and the known factors in a large cohort may achieve a better understanding of the prognostic value of RASD1 in B-ALL.…”

“…The immune phenotype was identified as previously described [20]. The cytogenetic analysis was performed with G-banding.…”

“…The molecular analyses for MLL rearrangement and IKZF1 deletion were performed as previously reported [17]. A positive status of MRD was defined as the detection of over 0.1% of cells displaying leukemia-associated aberrant immune phenotypes (LAIPs) analysed by flow cytometry [20]. MRD was monitored in all patients at regular intervals, including at the time of achieving CR, after every cycle of consolidation chemotherapy, and every 6 months during maintenance chemotherapy.…”

Targeting BACH2-FOS signaling overcomes chemoresistance via stromal microenvironment alterations in pediatric acute lymphoblastic leukemia

“…All mice were pre-treated with an intraperitoneal (i.p.) injection of CTX at a dose of 100 mg/kg once daily for two consecutive days (24). Mice were then injected intravenously (i.v.)…”