AUTHOR=Singh Jay , Kumari Sarita , Arora Mohit , Verma Deepak , Palanichamy Jayanth Kumar , Kumar Rajive , Sharma Gunjan , Bakhshi Sameer , Pushpam Deepam , Ali M. Shadab , Ranjan Amar , Tanwar Pranay , Chauhan Shyam S. , Singh Archna , Chopra Anita 

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

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.606370

DOI=10.3389/fonc.2021.606370

ISSN=2234-943X

ABSTRACT=<p>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 <italic>EMP1</italic>, <italic>CASP1</italic>, and <italic>NLRP3</italic> 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 <italic>EMP1</italic> along with a low expression of <italic>CASP1</italic> and <italic>NLRP3</italic> compared to disease free normal bone marrow collected from patients with solid tumors. Among the three analyzed genes, only <italic>EMP1</italic> 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 <italic>EMP1</italic> in BCR-ABL subtype. Expression of <italic>EMP1</italic> 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 <italic>CASP1</italic> high patients (p=0.048). In univariate survival analysis, higher <italic>EMP1</italic> expression was associated with poor prognostic measures while higher expression of <italic>NLRP3</italic> and <italic>CASP1</italic> was associated with better prognostic measures in our data. Further, multivariate analysis revealed an independent association of high <italic>CASP1</italic> and <italic>NLRP3</italic> with a better prognosis. This study strengthens the available evidence that mRNA expression of <italic>EMP1</italic>, <italic>CASP1</italic>, and <italic>NLRP3</italic> may serve as potential biomarkers for risk stratification of pediatric B-ALL patients.</p>