Prognostic Relevance of Expression of EMP1, CASP1, and NLRP3 Genes in Pediatric B-Lineage Acute Lymphoblastic Leukemia

Abstract

Glucocorticoid (GC), such as prednisolone, is an essential component of multidrug chemotherapy regimen for pediatric acute lymphoblastic leukemia (ALL). Resistance to GC in leukemia cells is associated with disease progression and poor prognosis. Despite the extensive use of GC for many years, molecular mechanisms underlying its resistance in ALL have not been fully uncovered. Recent studies have shown a potential role of EMP1, CASP1, and NLRP3 genes in prednisolone response. In this study on 148 pediatric B-ALL patients, we studied these three genes to assess their association with prednisolone response measured by day 8 blast count after 7 days of induction therapy with prednisolone. Intriguingly, ALL samples exhibited higher expression of EMP1 along with a low expression of CASP1 and NLRP3 compared to disease free normal bone marrow collected from patients with solid tumors. Among the three analyzed genes, only EMP1 was found to be overexpressed in prednisolone poor responders (p=0.015). Further, a comparison of gene expression between cytogenetic subtypes revealed higher expression of EMP1 in BCR-ABL subtype. Expression of EMP1 in multiple gene expression datasets was used for gene set enrichment analysis, which revealed TNF-α, IL-2-STAT5 signaling, inflammatory responses and hypoxia as the major positively associated pathways and E2F targets as negatively associated pathways. Interestingly, the clinical remission rate was higher in CASP1 high patients (p=0.048). In univariate survival analysis, higher EMP1 expression was associated with poor prognostic measures while higher expression of NLRP3 and CASP1 was associated with better prognostic measures in our data. Further, multivariate analysis revealed an independent association of high CASP1 and NLRP3 with a better prognosis. This study strengthens the available evidence that mRNA expression of EMP1, CASP1, and NLRP3 may serve as potential biomarkers for risk stratification of pediatric B-ALL patients.

Drug-tolerant persister B-cell precursor acute lymphoblastic leukemia cells

“…Elevated EMP1 is associated with prednisole resistance and worse outcome in BCP-ALL (36, 37). Interestingly, its expression is increased upon adhesion to stromal cells.…”

Insights Regarding the Role of Inflammasomes in Leukemia: What Do We Know?

“…Thus, ATRAinduced activation of CASP1 could serve as a suppressor in APL progression. Interestingly, high levels of mRNA of expression CASP1 were found in the clinical remission patient group, and CASP1 and NLRP3 expression were associated with better OS and EFS, respectively [88]. This indicates CASP1 and NLRP3 as potential biomarkers for risk stratification in ALL.…”

Prognostic utility of key copy number alterations in T cell acute lymphoblastic leukemia

“…These patients were initially treated with steroid prophase for 7 days and at day 8, absolute blast count was measured for assessment of prednisolone response. The patients were categorized into two groups into prednisolone good responder (PGR) and prednisolone poor responder (PPR) based on absolute blast count in PB on day 8 of initiation of therapy, as described previously 16 . Post‐induction BM samples were used for the assessment of minimal residual disease (MRD) as described in our previous publication 12 .…”

“…The patients were categorized into two groups into prednisolone good responder (PGR) and prednisolone poor responder (PPR) based on absolute blast count in PB on day 8 of initiation of therapy, as described previously. 16 Post-induction BM samples were used for the assessment of minimal residual disease (MRD) as described in our previous publication. 12 Patients with MRD <0.01% were considered as MRD negative and ≥0.01% as MRD positive.…”