Dataset Information

Aging-related proteome alterations in B cells may predispose for chronic lymphocytic leukemia - nuclear proteins of young B cells

ABSTRACT: Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is still incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. In order to get more detailed insights into CLL development, we performed a comprehensive proteome analysis of primary human CLL cells and B cells from young and age-matched healthy individuals. For comparison, we also analyzed the chronic B cell leukemia cell line JVM-13 showing rather limited similarity to the primary cells. A principal component analysis comprising 6945 proteins separated these four groups, placing B cells of aged-matched controls between those of young donors and CLL patients. Remarkably, B cells from aged controls displayed significant regulation of proteins related to metabolic processes and stress response in mitochondria such as DLAT, FIS1 and NDUFAB1 as well as DNA repair including RAD9A, MGMT and XPA. Interestingly, these alterations apparently correlating with aging of B cells may also be essential for tumorigenesis and were observed similarly in CLL cells. In CLL cells, in addition, some remarkable unique features like the loss of tumor suppressor molecules PNN and JARID2, and high expression of CCDC88A, PIGR and ID3 otherwise associated with epithelial mesenchymal transition and stemness were determined. Furthermore, while typical hallmarks of cancer such as cell proliferation were hardly apparent for CLL cells, alterations of metabolic enzymes were another outstanding feature in comparison to normal B cells, indicating increased beta-oxidation of fatty acids and increased consumption of glutamine. Targeted metabolomics assays corroborated these results. The present findings identify previously unrecognized features of CLL cells and suggest that aging may be accompanied by proteome alterations functionally relevant for predisposing B cells to transform to CLL cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Blood

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD006576 | Pride | 2017-12-05

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	B_cells_young_ne_1a.mgf	Mgf
	B_cells_young_ne_1a.mzid.gz	Mzid
	B_cells_young_ne_1a.pride.mgf.gz	Mgf
	B_cells_young_ne_1a.raw	Raw
	B_cells_young_ne_1b.mgf	Mgf

Items per page:

1 - 5 of 24

Publications

Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia.

Mayer Rupert L RL Schwarzmeier Josef D JD Gerner Marlene C MC Bileck Andrea A Mader Johanna C JC Meier-Menches Samuel M SM Gerner Samuel M SM Schmetterer Klaus G KG Pukrop Tobias T Reichle Albrecht A Slany Astrid A Gerner Christopher C

Molecular & cellular proteomics : MCP 20171201 2

B cell chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in adults, is still essentially incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. A comprehensive proteome analysis of primary human B-CLL cells and B cells from younger as well as elderly healthy donors was performed. For comparison, the chronic B cell leukemia cell line JVM-13 was also included. A principal component a ...[more]

PMID: 29196338

Similar Datasets

Project description:Acute myelogenous leukemia (AML) is driven by leukemic stem cells (LSC) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSC in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Amongst the targeted genes, we identified Mef2c, encoding a MADS transcription factor, and confirmed that over-expression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be upregulated in the mixed-lineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in AML patient samples with MLL gene disruptions, prompting an investigation of the causal interplay. Using a conditional mouse strain, we demonstrated that Mef2c deficiency does not impair the establishment nor maintenance of LSC generated in vitro by MLL/ENL fusion proteins â?? however, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included several genes encoding matrix metalloproteinases and chemokine ligands and receptors, providing a mechanistic link to increased homing and motility. Thus an early event in LSC generation may be responsible for the aggressive nature of this leukemia subtype. Experiment Overall Design: For gene expression profiling of M/E cells, RNA was isolated from M/E-Mef2c del/- cells infected with MYs-iPAC (empty vector) or MYs-pMef2cASR after puromycin selection at three different time points, pooled, and hybridized against the Agilent Whole Mouse Genome Microarray 4x44K using the one-color service of Miltenyi. Transcript levels were verified by real-time RT-PCR using the SYBRGreen Reaction Mix (Roche Mannheim) in a Roche Light-Cycler. cDNA levels were normalized against Hprt transcript levels. Primers and amplification conditions are available upon request.