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Functional loss of I?B? leads to NF-?B deregulation in aggressive chronic lymphocytic leukemia.

ABSTRACT: NF-?B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-?B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I?B?, a negative regulator of NF-?B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced I?B? protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that I?B? loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-?B deregulation during lymphomagenesis.

SUBMITTER: Mansouri L

PROVIDER: S-EPMC4451125 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.

Mansouri Larry L Sutton Lesley-Ann LA Ljungström Viktor V Bondza Sina S Arngården Linda L Bhoi Sujata S Larsson Jimmy J Cortese Diego D Kalushkova Antonia A Plevova Karla K Young Emma E Gunnarsson Rebeqa R Falk-Sörqvist Elin E Lönn Peter P Muggen Alice F AF Yan Xiao-Jie XJ Sander Birgitta B Enblad Gunilla G Smedby Karin E KE Juliusson Gunnar G Belessi Chrysoula C Rung Johan J Chiorazzi Nicholas N Strefford Jonathan C JC Langerak Anton W AW Pospisilova Sarka S Davi Frederic F Hellström Mats M Jernberg-Wiklund Helena H Ghia Paolo P Söderberg Ola O Stamatopoulos Kostas K Nilsson Mats M Rosenquist Richard R

The Journal of experimental medicine 20150518 6

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift del ...[more]

PMID: 25987724

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Project description: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.

Dataset Information

Functional loss of I?B? leads to NF-?B deregulation in aggressive chronic lymphocytic leukemia.

Publications

Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia.

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