Dataset Information

HSP90 overexpression potentiates the B-cell receptor and fibroblast growth factor receptor survival signals in chronic lymphocytic leukemia cells.

ABSTRACT: Chronic lymphocytic leukemia (CLL) is still an incurable disease despite aggressive chemotherapies including the B-cell receptor (BCR) targeted-inhibitors. Therefore, we assessed the expression status of key signal mediators of the BCR pathway in CLL cells. Indeed, we detected aberrantly elevated levels of CD79a, B-cell adaptor for PI3K (BCAP) and phospholipase C (PLC)?2, key mediators of BCR signal, in CLL cells. As HSP90 is also overexpressed in CLL cells, we hypothesized that HSP90 could potentiate the BCR signal via stabilization of multiple key components of the BCR-signalosome. We found that HSP90 formed a multi-molecular complex with CD79a, BCAP, PLC?2, LYN, SYK, Bruton tyrosine kinase (BTK) and AKT and that, pharmacologic inhibition or partial depletion of HSP90 reduced the expression of these signal mediators in CLL cells. In addition, our findings also demonstrated that HSP90 could stabilize the tyrosine phosphatase, PTPN22 which positively regulates AKT phosphorylation, and the constitutively active fibroblast growth factor receptor 3 (FGFR3) in CLL cells. Finally, HSP90 inhibition induced apoptosis in CLL cells in a dose-dependent manner likely via downregulation of anti-apoptotic proteins MCL-1 and XIAP, but not BCL2, reported to be overexpressed in CLL cells. In total, our findings suggest that HSP90-inhibition may sensitize the leukemic B-cells to BCR-targeted agents, particularly those become resistant to these therapies.

SUBMITTER: Mahmud H

PROVIDER: S-EPMC7275782 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundChronic lymphocytic leukemia (CLL) is the most frequent, and still incurable, form of leukemia in the Western World. It is widely accepted that cancer results from an evolutionary process shaped by the acquisition of driver mutations which confer selective growth advantage to cells that harbor them. Clear examples are missense mutations in classic RAS genes (KRAS, HRAS and NRAS) that underlie the development of approximately 13% of human cancers. Although autonomous B cell antigen receptor (BCR) signaling is involved and mutations in many tumor suppressor genes and oncogenes have been identified, an oncogenic driver gene has not still been identified for CLL.MethodsConditional knock-in mice were generated to overexpress wild type RRAS2 and prove its driver role. RT-qPCR analysis of a human CLL sample cohort was carried out to measure RRAS2 transcriptional expression. Sanger DNA sequencing was used to identify a SNP in the 3'UTR region of RRAS2 in human CLL samples. RNAseq of murine CLL was carried out to identify activated pathways, molecular mechanisms and to pinpoint somatic mutations accompanying RRAS2 overexpression. Flow cytometry was used for phenotypic characterization and shRNA techniques to knockdown RRAS2 expression in human CLL.ResultsRRAS2 mRNA is found overexpressed in its wild type form in 82% of the human CLL samples analyzed (n = 178, mean and median = 5-fold) as well as in the explored metadata. A single nucleotide polymorphism (rs8570) in the 3'UTR of the RRAS2 mRNA has been identified in CLL patients, linking higher expression of RRAS2 with more aggressive disease. Deliberate overexpression of wild type RRAS2 in mice, but not an oncogenic Q72L mutation in the coding sequence, provokes the development of CLL. Overexpression of wild type RRAS2 in mice is accompanied by a strong convergent selection of somatic mutations in genes that have been identified in human CLL. R-RAS2 protein is physically bound to the BCR and mediates BCR signals in CLL.ConclusionsThe results indicate that overexpression of wild type RRAS2 is behind the development of CLL.

Dataset Information

HSP90 overexpression potentiates the B-cell receptor and fibroblast growth factor receptor survival signals in chronic lymphocytic leukemia cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets