Resistance to CD95-mediated apoptosis of CD40-activated chronic lymphocytic leukemia B cells is not related to lack of DISC molecules expression

Totero, Daniela de; Montera, Mariapina; Rosso, Ombretta; Clavio, Marino; Balleari, Enrico; Foà, Robin; Gobbi, Marco

doi:10.1038/sj.thj.6200362

Cited by 17 publications

(14 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4 It can be speculated that TOSO down-regulation is an early event in the apoptotic cascade, but Bid expression is a conditio sine qua non for the full activation of apoptosis in CLL cells. In contrast to results obtained after CD40 activation, we could demonstrate in our study that BCR stimulation resulted in up-regulation of TOSO in CLL cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

Pallasch¹,

Schulz²,

Kutsch³

et al. 2008

Blood

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

“…3 Regarding the extrinsic apoptosis pathway, CLL cells exhibit resistance toward Fas-mediated apoptosis. Although CLL cells express Fas and DISC-related molecules, 4 they remain resistant toward Fasinduced apoptosis. Inducing Fas expression failed to increase Fas-mediated apoptosis in CLL.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

Pallasch¹,

Schulz²,

Kutsch³

et al. 2008

Blood

View full text Add to dashboard Cite

“…[20][21][22][23] Previous studies have demonstrate that CLL cells are resistant to Fas mediated apoptosis. 8,23 BCL-2 overexpression is a known mechanism for intrinsic apoptosis resistance in CLL. 10 We postulated that TOSO might be associated with BCL-2 deregulation and evaluated FLIP as a possible up-stream regulator of TOSO expression.…”

Section: Resultsmentioning

confidence: 99%

“…Among the antiapoptotic genes, the IPA analysis identified a 4-fold overexpression of FAIM3 (TOSO), a transmembrane protein that colocalizes with Fas and binds specifically to FADD, inhibiting procaspase 8 and inducing resistance to Fas-mediated apoptosis. [20][21][22][23] Previous studies have demonstrate that CLL cells are resistant to Fas mediated apoptosis. 8,23 BCL-2 overexpression is a known mechanism for intrinsic apoptosis resistance in CLL.…”

mentioning

confidence: 99%

SAGE analysis demonstrates increased expression of TOSO contributing to Fas-mediated resistance in CLL

Proto‐Siqueira

Panepucci

Careta

et al. 2008

Blood

View full text Add to dashboard Cite

To identify novel genes involved in the molecular pathogenesis of chronic lymphocytic leukemia (CLL) we performed a serial analysis of gene expression (SAGE) in CLL cells, and compared this with healthy B cells (nCD19 ؉ ). We found a high level of similarity among CLL subtypes, but a comparison of CLL versus nCD19 ؉ libraries revealed 55 genes that were overrepresented and 49 genes that were downregulated in CLL. A gene ontology analysis revealed that TOSO, which plays a functional role upstream of Fas extrinsic apoptosis pathway, was over-expressed in CLL cells. This finding was confirmed by real-time reverse transcriptionpolymerase chain reaction in 78 CLL and 12 nCD19 ؉ cases (P < .001). We validated expression using flow cytometry and tissue microarray and demonstrated a 5.6-fold increase of TOSO protein in circulating CLL cells (P ‫؍‬ .013) and lymph nodes (P ‫؍‬ .006). Our SAGE results have demonstrated that TOSO is a novel overexpressed antiapoptotic gene in CLL. IntroductionChronic lymphocytic leukemia (CLL) is characterized by the accumulation of small mature B cells, mostly in early G1-phase, 1 that display typical B-cell surface markers in addition to CD5. Two subtypes of CLL are defined by either mutated or unmutated IgVH genes and this has prognostic significance. 2 Studies have revealed surrogate markers for the IgVH status in CLL cases, [3][4][5] but microarray studies demonstrated relatively few differences in gene expression between the 2 subtypes, 6,7 suggesting that the cells arise from a common cell of origin.CLL pathogenesis has been linked to a failure of the malignant cells to undergo apoptosis. Apoptosis resistance stems from a combination of microenvironmental survival signals (extrinsic pathway) as well as intrinsic alterations of the apoptotic machinery within the CLL cell. 8,9 BCL-2 is present at increased levels in more than 80% of CLL cases. The mechanism for this was recently elucidated by the demonstration that miR15 and miR16 inhibit BCL-2 at a posttranscriptional level in CLL. 10 The extrinsic apoptosis pathway is regulated by Fas membrane activation, and CLL cells display resistance to apoptosis driven by anti-Fas treatment. Although CLL cells express low levels of Fas, an upstream event might be responsible for this phenotype. 8,9 The search for differentially expressed genes has mainly been performed by DNA-array studies 6,7,11 and, although powerful, this methodology investigates only known genes. To evaluate for new mechanisms involved in apoptosis resistance of CLL cells, we performed a serial analysis of gene expression (SAGE) in CLL samples and identified that TOSO (regulator of FAS-induced apoptosis) is aberrantly expressed in CLL cells. Methods Patients and controlsPeripheral blood (PB) was obtained from 78 CLL patients, who met the diagnostic criteria for CLL. 12 Eight untreated and early stage (Binet A/Rai I) CLL patients (4 mutated and 4 unmutated) where selected for construction of SAGE libraries from their cells. PB of 12 healthy blood donors was used as a source...

show abstract

“…[1][2][3][4] CD95, as prototypical member of the tumor necrosis factor superfamily, is able to transmit a death signal to the cell upon binding of the CD95 ligand (CD95L). 5 CD95 is involved in fundamental processes like the maturation or homeostasis of lymphocytes, as well as the elimination of virus-infected or malignant cells.…”

Section: Introductionmentioning

confidence: 99%

miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL

Berg

Rusch

Vartak

et al. 2015

Blood

View full text Add to dashboard Cite

Key Points• APTs as miRNA targets provide a novel molecular mechanism for how primary CLL cells escape from CD95-mediated apoptosis.• Palmitoylation as a novel posttranslational modification in CLL might also impact on survival signaling, proliferation, and migration.Resistance toward CD95-mediated apoptosis is a hallmark of many different malignancies, as it is known from primary chronic lymphocytic leukemia (CLL) cells. Previously, we could show that miR-138 and -424 are downregulated in CLL cells. Here, we identified 2 new target genes, namely acyl protein thioesterase (APT) 1 and 2, which are under control of both miRs and thereby significantly overexpressed in CLL cells. APTs are the only enzymes known to promote depalmitoylation. Indeed, membrane proteins are significantly less palmitoylated in CLL cells compared with normal B cells. We identified APTs to directly interact with CD95 to promote depalmitoylation, thus impairing apoptosis mediated through CD95. Specific inhibition of APTs by siRNAs, treatment with miRs-138/-424, and pharmacologic approaches restore CD95-mediated apoptosis in CLL cells and other cancer cells, pointing to an important regulatory role of APTs in CD95 apoptosis. The identification of the depalmitoylation reaction of CD95 by APTs as a microRNA (miRNA) target provides a novel molecular mechanism for how malignant cells escape from CD95-mediated apoptosis. Here, we introduce palmitoylation as a novel posttranslational modification in CLL, which might impact on localization, mobility, and function of molecules, survival signaling, and migration. (Blood. 2015;125(19):2948-2957 IntroductionChronic lymphocytic leukemia (CLL) cells are characterized by a distinct resistance toward CD95 (Fas/APO-1).1-4 CD95, as prototypical member of the tumor necrosis factor superfamily, is able to transmit a death signal to the cell upon binding of the CD95 ligand (CD95L). 5CD95 is involved in fundamental processes like the maturation or homeostasis of lymphocytes, as well as the elimination of virus-infected or malignant cells. Malignant cells might develop resistance mechanisms to escape from CD95-mediated apoptosis, either by silencing its expression, 6 by mutation, 7 or by overexpression of antiapoptotic proteins.2 Prior studies emphasized that proper CD95-mediated apoptotic signaling might depend on posttranslational modifications of CD95. [8][9][10][11] This is of particular interest because the nature of molecular events downstream of the death-inducing signaling complex is well investigated, but the knowledge of initial events, especially at the plasma membrane, remains poorly defined. It was shown that palmitoylation, a common posttranslational modification, is crucial for localization of CD95 to specialized membrane microdomains and for formation of stable receptor aggregates. 8,9 Palmitoylation is the only reversible lipid modification, indicating that it is involved in dynamic processes.12-14 Overall, proteome analyses identified .1000 proteins to be palmitoylated. These proteins are invol...

show abstract

Resistance to CD95-mediated apoptosis of CD40-activated chronic lymphocytic leukemia B cells is not related to lack of DISC molecules expression

Cited by 17 publications

References 35 publications

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

Overexpression of TOSO in CLL is triggered by B-cell receptor signaling and associated with progressive disease

SAGE analysis demonstrates increased expression of TOSO contributing to Fas-mediated resistance in CLL

miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL

Contact Info

Product

Resources

About