Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and <i>V3-21</i> Usage Characterize Discordance of ZAP-70 and <i>VH</i> Mutation Status in Chronic Lymphocytic Leukemia

Kröber, Alexander; Bloehdorn, Johannes; Häfner, Sebastian; Bühler, Andreas; Seiler, Till; Kienle, Dirk; Winkler, Dirk; Bangerter, Markus; Schlenk, Richard F.; Benner, Axel; Lichter, Peter; Döhner, Hartmut; Stilgenbauer, Stephan

doi:10.1200/jco.2005.03.7184

Cited by 179 publications

(145 citation statements)

References 32 publications

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“…In our study it was also found that there was a very good correlation between ZAP-70 expression and IgV H mutations and, not surprisingly, that ZAP-70 had a prognostic value equivalent to that of IgV H mutations (20). Afterwards, many other groups have reproduced these results (20,22,(25)(26)(27)(28)(29)(30) (Tables 1 and 2). The reasons for discrepant cases, which range from 8 to 25%, are not fully understood.…”

Section: Zap-70 Expressionsupporting

confidence: 73%

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Clinical implications of ZAP‐70 expressionin chronic lymphocytic leukemia

Bosch

Muntañola

Giné

et al. 2006

Cytometry Part B Clinical

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Section: Zap-70 Expressionsupporting

confidence: 73%

“…The various reports, however, differ in the methods used to determine ZAP-70 expression. Recently, Krober et al have shown that unmutated CLL cases with high expression of ZAP-70 frequently present other biological features such as del(17p) conveying poor prognosis (27).…”

Section: Zap-70 Expressionmentioning

confidence: 99%

Clinical implications of ZAP‐70 expressionin chronic lymphocytic leukemia

Bosch

Muntañola

Giné

et al. 2006

Cytometry Part B Clinical

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“…Mean and SEM of 18 individual CLL samples measured in duplicate or triplicate (samples no. 2,6,8,15,17,18,19,21,24,28,33,36,39,40,41,43,48,50) are shown; **p < 0.001; *p < 0.05; (right) Graph illustrates specific cell death upon treatment with 10 mM Fludarabine or BV6 of genomic subgroups including norm/13q-, IGVH non-mutated, tp53 mutated and 17p deletion. (e and f) BV6-sensitive primary CLL cells were co-treated with 10 mM BV6 and 1,000 ng/ml CD40 ligand (e) or stimulated with BV6 in normal or conditioned medium at indicated concentrations (f) for 48 hr.…”

Section: Bv6 Induces Cell Death In Primary Cll Cells Irrespective Of mentioning

confidence: 99%

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Opel

Schnaiter

Dodier

et al. 2015

Intl Journal of Cancer

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Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-jB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-jB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)a, as zVAD.fmk, necrostatin-1 or TNFa-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world. 1 Key prognostic factors besides the Rai and Binet stage are chromosomal aberrations like 17p or 11q deletion, TP53 mutation and immunoglobulin heavy-chain variable region gene (IGVH) mutation status. Although individualized therapeutic strategies have been developed, the disease is still incurable. Especially patients with 17p deletion and TP53 mutation have a very poor prognosis. 2 Therefore, new therapeutic targets that act independently of functional p53 in CLL are needed.CLL is characterized by the accumulation of Blymphocytes which has been largely attributed to defective cell death pathways rather than to aberrant proliferation. [3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3. 7 Inhibitor of apoptosis (IAP) proteins are major regulators of cell death and survival processes. X-linked inhibitor of apoptosis (XIAP) acts as direct caspase inhibitor, 8 while cIAP1 and -2 were shown to protect cells from cell death by acting primarily as E3 ubiquitin liga...

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“…Molecular genetics characterization, including the detection of genomic aberrations by fluoresence in situ hybridization and the determination of IgVH status by sequencing, as well as the determination of ZAP-70 expression were performed as previously described. 5,19 …”

Section: Samples From Patients With Cllmentioning

confidence: 99%

“…1 Although several novel therapeutic approaches have entered the clinic and show high response rates in patients with CLL, most of them do not prolong overall survival, 2,3 which strongly depends on a number of prognostic factors. 4,5 Therefore, novel therapeutic options are desirable, especially for patients bearing negative prognostic markers such as cytogenetic aberrations (del17p and del11q), 6 unmutated IgVH gene status 7 or high ZAP-70 expression. 8 The clinical course of disease is heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

et al. 2010

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The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8 þ T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM þ CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2 þ CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 lg per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 lg per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I1 skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8 þ T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8 þ T cells that expressed high levels of CD107a and produced both interferon-c and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8 þ T-cell responses against the tumor antigen RHAMM.

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Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

Cited by 179 publications

References 32 publications

Clinical implications of ZAP‐70 expressionin chronic lymphocytic leukemia

Clinical implications of ZAP‐70 expressionin chronic lymphocytic leukemia

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia

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