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

Pallasch, Christian P.; Schulz, Alexandra; Kutsch, Nadine; Schwamb, Janine; Hagist, Susanne; Kashkar, Hamid; Ultsch, Alfred; Wickenhauser, Claudia; Hallek, Michael; Wendtner, Clemens‐Martin

doi:10.1182/blood-2008-05-157255

Cited by 49 publications

(40 citation statements)

References 25 publications

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“…6,27 Other studies found that high levels of TOSO expression were correlated with more aggressive leukemia associated with high white blood cell (WBC) counts, advanced Binet stage, unmutated IGHV, and the need for chemotherapy. 28,29 Gene microarray studies also indicated selective expression of TOSO by naive and memory B cells in tonsils, 33 the findings being consistent with our protein expression data. 25 Our results indicate that surface FcR levels on CLL B cells as determined by both HM14 anti-FcR and 1E4 anti-TOSO mAbs are significantly higher in MT-CLL than UM-CLL and that the discrepancy in the different studies could be because of the detection methods used rather than the patient populations examined in different countries (England, Germany, and the United States).…”

Section: Discussionsupporting

confidence: 89%

“…Several studies also have demonstrated enhanced expression of FAIM3/TOSO, the former designations of the FCMR gene, in CLL. 6,[27][28][29]31,32 Two studies found no correlation of TOSO expression levels with prognostic factors, including IGHV mutational status, cytogenetics, and previous treatment. 6,27 Other studies found that high levels of TOSO expression were correlated with more aggressive leukemia associated with high white blood cell (WBC) counts, advanced Binet stage, unmutated IGHV, and the need for chemotherapy.…”

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confidence: 99%

“…25 This incorrect designation has led to the misconception that enhanced FAIM3/TOSO expression by CLL cells may be linked to their resistance to cell death mechanisms. [27][28][29] Here, we examined the expression of FcR in CLL patients using receptorspecific mAbs and have shown the enhanced expression of both the membrane-bound and soluble form of the receptor. …”

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confidence: 99%

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Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcμR) in patients with chronic lymphocytic leukemia

Li¹,

Kubagawa²,

McCollum³

et al. 2011

Blood

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The association of an IgM-Fc receptor (FcR) with chronic lymphocytic leukemia (CLL) was suggested more than 30 years ago, but its authenticity has never been formally addressed. We exam IntroductionChronic lymphocytic leukemia (CLL) is the most common leukemia of adults in Western countries and accounts for ϳ 30% of all cases of leukemia in the United States. It is a heterogeneous leukemia that is thought to originate from antigen-stimulated B cells that escape from normal cell death mechanisms. 1,2 Survival of CLL patients ranges from a few years to several decades. The most reliable marker thus far for predicting the prognosis of CLL is the mutation status in the immunoglobulin heavy chain variable region (IGHV). Unmutated (UM)-CLL is aggressive and mutated (MT)-CLL is more indolent. [3][4][5] Because DNA sequencing is not practical for most clinical laboratories, various cell surface and intracellular proteins have been explored as potential surrogate markers. ZAP-70, a Syk family tyrosine kinase normally expressed in T cells, has proved to be a very good indicator for UM-CLL, but the required intracellular staining is technically challenging and results in diagnostic inconsistency among clinical laboratories. [6][7][8][9][10][11] Other markers, including membrane proteins (eg, CD38, Fc receptor-like protein 2) and serum proteins (eg, thymidine kinase, soluble CD23, and ␤2-microglobulin), also have been studied as surrogate prognostic indicators. 3,4,[12][13][14][15][16][17] The association of the IgM Fc receptor (FcR) with CLL has long been suggested based on the ability of CLL cells to form rosettes with IgM-coated erythrocytes. [18][19][20][21][22] Unfortunately, this early intriguing suggestion was not pursued thereafter, probably because of uncertainties with such a crude detection procedure. During the course of analysis of B-cell activation antigens with the BAC-1 mouse IgM monoclonal antibody (mAb), we serendipitously found an IgM-binding protein of ϳ 60 kDa that was expressed on CLL B cells and activated normal B cells by immunofluorescence and biochemical analyses using various IgM ligands. 23,24 The gene encoding an authentic FcR has defied identification until our recent discovery of a bona fide FcR cDNA in the B-lineage libraries, including one library derived from CLL B cells. 25 Surprisingly, the corresponding FCMR gene had been already reported as TOSO or Fas apoptosis inhibitory molecule 3 (FAIM3). 26 Notably, the reported inhibition of apoptosis was based on an assay in which apoptosis was induced by ligation of Fas on the Jurkat T-cell line with a mouse IgM mAb (CH11). Our results indicated that FcR per se had no inhibitory activity in Fas-mediated apoptosis and that such inhibition was only achieved when anti-Fas mAb of an IgM but not IgG isotype was used for inducing apoptosis. 25 This incorrect designation has led to the misconception that enhanced FAIM3/TOSO expression by CLL cells may be linked to their resistance to cell death mechanisms. [27][28][29] Here, we examined the expression...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcμR) in patients with chronic lymphocytic leukemia

Li¹,

Kubagawa²,

McCollum³

et al. 2011

Blood

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“…34 High expression of TOSO, also called Fas inhibitory molecule 3, is associated with unfavorable prognosis and may explain resistance of CLL cells to Fas-induced apoptosis. 35 In addition, expression of BCL2 family genes (BCL2, MCL1, BIM, BMF and NOXA) and p53-dependent genes (p53, p21 and PUMA) in CD19-purified CLL cells after 24 h actinomycin D treatment was assessed using RT-PCR. No influence of the CD19-purification process on the expression of the tested genes could be observed (Supplementary Figure 8).…”

Section: Identification Of P53-independent Apoptosis Inducersmentioning

confidence: 99%

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

et al. 2012

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Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.

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“…The procedures for HS-5 bone marrow stroma coculture, B-cell receptor and CD40L stimulation were performed as described. 15 …”

Section: Patient Samples and Cell Culturementioning

confidence: 99%

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

Kruse¹,

Pallasch

Bantscheff³

et al. 2010

Leukemia

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The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia (CLL). We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells. Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c-KIT, FLT3, BTK and SYK were comparatively inactive, the CDK inhibitors BMS-387032 and flavopiridol showed marked efficacy similar to staurosporine. Using the kinobeads proteomics method, kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells. The targets most potently affected were CDK9, cyclin T1, AFF3/4 and MLLT1, which may represent four subunits of a deregulated positive transcriptional elongation factor (p-TEFb) complex. Albeit with lower potency, both drugs also bound the basal transcription factor BTF2/TFIIH containing CDK7. Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development.

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

Cited by 49 publications

References 25 publications

Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcμR) in patients with chronic lymphocytic leukemia

Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcμR) in patients with chronic lymphocytic leukemia

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

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