Aspartic Aminopeptidase Is a Novel Biomarker of Aggressive Chronic Lymphocytic Leukemia

Abstract

Treatment of chronic lymphocytic leukemia has advanced substantially as our understanding of the kinase signal transduction pathways driven by the B cell receptor (BcR) has developed. Particularly, understanding the role of Bruton tyrosine kinase and phosphatidyl inositol 3 kinase delta in driving prosurvival signal transduction in chronic lymphocytic leukemia (CLL) cells and their targeting with pharmacological inhibitors (ibrutinib and idelalisib, respectively) has improved patient outcomes significantly. The kinase signaling pathway induced by the BcR is highly complex and has multiple interconnecting branches mediated by tyrosine and serine/threonine kinases activated downstream of the BcR. There is a high level of redundancy in the biological responses, with several BcR-signaling kinases driving nuclear factor kappa B activation or inducing antiapoptotic Bcl-2 genes. Accordingly, common gene targets of BcR-signaling kinases may serve as biomarkers indicating enhanced BCR-signaling and aggressive disease progression. This study used a gene expression correlation analysis of malignant B cell lines and primary CLL cells to identify genes whose expression correlated with BCR-signaling kinases overexpressed and/or overactivated in CLL, namely: AKT1, AKT2, BTK, MAPK1, MAPK3, PI3KCD and ZAP70. The analysis identified a 32-gene signature with a strong prognostic potential and DNPEP, the gene coding for aspartic aminopeptidase, as a predictor of aggressive CLL. DNPEP gene expression correlated with MAPK3, PI3KCD, and ZAP70 expression and, in the primary CLL test dataset, showed a strong prognostic potential. The inhibition of DNPEP with a pharmacological inhibitor enhanced the cytotoxic potential of idelalisib and ibrutinib, indicating a biological functionality of DNPEP in CLL. DNPEP, as an aminopeptidase, contributes to the maintenance of the free amino acid pool in CLL cells found to be an essential process for the survival of many cancer cell types, and thus, these results warrant further research into the exploitation of aminopeptidase inhibitors in the treatment of drug-resistant CLL.

Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

“…ANPEP is also expressed in a subset of Waldenström macroglobulinemia, MM, and plasma cell leukemias [9,10]. ANPEP expression in samples from MM patients has been shown to correlate with shorter overall survival [11,12]. Recently, endoplasmic reticulum aminopeptidase 2 (ERAP2) expression has been associated with a better outcome in patients with bladder cancer treated with immunotherapies [13].…”

Molecular characterization of a novel aspartyl aminopeptidase that contributes to the increase in glutamic acid content in chicken meat during cooking

“…Although it has been implicated in the metabolism of angiotensin peptides ( Chen et al, 2012 ), its biological and pathological roles remain poorly studied ( Chen et al, 2014 ). Recently it was found that DNPEP is a novel biomarker of aggressive chronic lymphocytic leukemia ( Kakodkar et al, 2020 ).…”

Deciphering the SOX4/MAPK1 regulatory axis: a phosphoproteomic insight into IQGAP1 phosphorylation and pancreatic Cancer progression

“…SOX4 is a transcription factor involved in multiple biological processes, including cell proliferation, differentiation, and migration [ 13 ]. MAPK1, a kinase, is pivotal in numerous signaling pathways [ 14 ]. IQGAP1 is a versatile protein involved in cell cytoskeleton remodeling, cell migration, and intercellular signaling [ 15 ].…”