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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy [1]
In this study on 148 B-acute lymphoblastic leukemia (ALL) pediatric patients from India, which were treated with ICiCLe protocol, we aimed to evaluate the association between response to prednisolone of ALL patients, as assessed by day 8
Post induction Minimal residual disease (MRD) was evaluated in 145 patients out of which 27 (18.62%) were MRD positive, while 3 patients were inevaluable for MRD
Summary
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy [1]. The prognosis of ALL has improved tremendously with the advent of modern combination chemotherapy, amongst which, prednisolone (PRD) serves as an integral component [2, 3]. PRD is a glucocorticoid (GC) that exerts its cytotoxic effect on leukemic cells through induction of apoptosis. It has been known over the last 5-6 decades that PRD can induce remission in ALL patients [4]. The response to PRD is evaluated by either assessing the absolute number of blasts in the peripheral blood (PB) of the patients on day 8 of induction chemotherapy or by in vitro methyl thiazole tetrazolium (MTT) assay on primary culture of leukemic cells collected at the time of diagnosis [2, 3, 5, 6]. Poor responders receive intensified therapy, both during the induction and at later phases of the treatment
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