Publications by authors named "Christine Damm-Welk"

30 Publications

  • Page 1 of 1

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Nat Commun 2021 09 22;12(1):5577. Epub 2021 Sep 22.

Division of Haematopathology, European Institute of Oncology IRCCS, Milan, Italy.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.
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http://dx.doi.org/10.1038/s41467-021-25379-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458384PMC
September 2021

Minimal Disease Monitoring in Pediatric Non-Hodgkin's Lymphoma: Current Clinical Application and Future Challenges.

Cancers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Minimal residual disease (MRD) detection is established routine practice for treatment stratification in leukemia and used for treatment optimization in adult lymphomas. Minimal disease studies in childhood non-Hodgkin lymphomas are challenged by stratified treatment in different subtypes, high cure rates, low patient numbers, limited initial tumor material, and early progression. Current clinical applications differ between the subtypes. A prognostic value of minimal disseminated disease (MDD) could not yet be clearly established for lymphoblastic lymphoma using flow cytometry and PCR-based methods for T-cell receptor (TCR) or immunoglobulin (IG) rearrangements. fusion sequences or IG rearrangements enable minimal disease detection in Burkitt lymphoma and -leukemia. An additional prognostic value of MDD in Burkitt lymphoma and early MRD in Burkitt leukemia is implicated by single studies with risk-adapted therapy. MDD and MRD determined by PCR for ALK-fusion transcripts are independent prognostic parameters for patients with ALK-positive anaplastic large cell lymphoma (ALCL). They are introduced in routine clinical practice and used for patient stratification in clinical studies. Early MRD might serve as an endpoint for clinical trials and for guiding individual therapy. Validation of MDD and MRD as prognostic parameters is required for all subtypes but ALCL. Next-generation sequencing-based methods may provide new options and applications for minimal disease evaluation in childhood lymphomas.
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http://dx.doi.org/10.3390/cancers13081907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071445PMC
April 2021

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively ( < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.
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http://dx.doi.org/10.3390/cancers12102747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598675PMC
September 2020

Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target.

Haematologica 2021 06 1;106(6):1693-1704. Epub 2021 Jun 1.

Department of Paediatric Oncology, Addenbrooke Hospital, Cambridge, UK.

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.
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http://dx.doi.org/10.3324/haematol.2019.238766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168516PMC
June 2021

Quantification of minimal disseminated disease by quantitative polymerase chain reaction and digital polymerase chain reaction for as a prognostic factor in children with anaplastic large cell lymphoma.

Haematologica 2020 08 24;105(8):2141-2149. Epub 2019 Oct 24.

NHL-BFM Study Center, Department of Pediatric Hematology and Oncology, Giessen, Germany

Detection of minimal disseminated disease is a validated prognostic factor in ALK-positive anaplastic large cell lymphoma. We previously reported that quantification of minimal disease by quantitative real-time polymerase chain reaction (RQ-PCR) in bone marrow applying a cut-off of 10 copies 10 copies of identifies very high-risk patients. In the present study, we aimed to confirm the prognostic value of quantitative minimal disseminated disease evaluation and to validate digital polymerase chain reaction (dPCR) as an alternative method. Among 91 patients whose bone marrow was analyzed by RQ-PCR, more than 10 normalized copy-numbers correlated with stage III/IV disease, mediastinal and visceral organ involvement and low anti-ALK antibody titers. The cumulative incidence of relapses of 18 patients with more than 10 normalized copy-numbers of was 61±12% compared to 21±5% for the remaining 73 patients (=0.0002). Results in blood correlated with those in bone marrow (r=0.74) in 70 patients for whom both materials could be tested. Transcripts were quantified by RQ-PCR and dPCR in 75 bone marrow and 57 blood samples. Copy number estimates using dPCR and RQ-PCR correlated in 132 samples (r=0.85). Applying a cut-off of 30 copies /10 copies for quantification by dPCR, almost identical groups of patients were separated as those separated by RQ-PCR. In summary, the prognostic impact of quantification of minimal disseminated disease in bone marrow could be confirmed for patients with anaplastic large cell lymphoma. Blood can substitute for bone marrow. Quantification of minimal disease by dPCR provides a promising tool to facilitate harmonization of minimal disease measurement between laboratories and for clinical studies.
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http://dx.doi.org/10.3324/haematol.2019.232314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395281PMC
August 2020

NPM-ALK-reactive T-cell responses in children and adolescents with NPM-ALK positive anaplastic large cell lymphoma.

Oncoimmunology 2019;8(9):e1625688. Epub 2019 Jun 26.

Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany.

The oncoantigen nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces cellular and humoral immune responses in patients with NPM-ALK-positive anaplastic large cell lymphoma (ALCL). We characterize the NPM-ALK-specific T-cell responses in a cohort of pediatric and adolescent ALCL-patients in remission without Human Leucocyte Antigen (HLA)-preselection. First, we assessed NPM-ALK-reactive T-cell responses and their HLA-class I restriction in patients by using dendritic cells (DCs) transfected with transcribed (IVT) NPM-ALK-RNA for CD8 (n = 20) or CD3 (n = 9) T-cell stimulation. NPM-ALK-specific T-cells were detected in twelve of 29 patients (nine of 20 with CD8-selected and three of nine with CD3-selected cells). Recognition of NPM-ALK was restricted by HLA-C alleles in six of eight, and by HLA-B alleles in four of eight analyzed patients. No NPM-ALK-reactivity was detected in 20 healthy individuals. Second, in order to define possible immunogenic NPM-ALK-epitope regions, DCs pulsed with pools of overlapping long NPM-ALK-peptides were used to stimulate T-cells in further 22 patients and ten controls. Responsive T-cells were detected in 15 patients and in five controls. A peptide pool located in the middle of the kinase domain induced ALK-reactive T-cells in 14 of 15 responsive patients. We could narrow to single peptides between p327-p370 of NPM-ALK in four patients. In conclusion, using IVT-RNA, 40% of NPM-ALK-positive ALCL-patients in remission had detectable NPM-ALK-specific T-cell responses which were mainly restricted by HLA-B and -C alleles. Peptide stimulation of T-cells revealed responses in almost 70% of patients and allowed describing an immunogenic region located in the ALK-kinase domain.
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http://dx.doi.org/10.1080/2162402X.2019.1625688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685518PMC
February 2021

Epitope mapping of anti-ALK antibodies in children with anaplastic large cell lymphoma.

Clin Immunol 2018 10 1;195:77-81. Epub 2018 Aug 1.

Dept. of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany. Electronic address:

Patients with Nucleophosmin (NPM)-Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount ALK autoantibodies. The titer of these autoantibodies inversely correlates with the risk of relapse. The epitopes recognized by these autoantibodies in NPM-ALK might be associated with different ALK-antibody levels. We used overlapping peptide microarray technology to analyze epitope-binding to NPM-ALK by plasma or serum from 129 ALK-positive ALCL patients and 21 controls. Antibodies present in sera from ALCL patients bound to epitopes mainly in the C-terminal region of the ALK portion of NPM-ALK (amino acid positions 469-496, 561-588, 617-644). Patients with higher ALK antibody titers detected the epitope 561-588 more frequently as well as three further epitopes at the N-terminus of the kinase domain compared to patients with intermediate and low titers. These results identify new potential target epitopes for immunotherapy in ALK-positive ALCL. The methodology can be adapted for more reproducible analyses of tumor antigen detection.
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http://dx.doi.org/10.1016/j.clim.2018.07.008DOI Listing
October 2018

Characterization and diagnostic application of genomic fusion sequences in anaplastic large-cell lymphoma.

Oncotarget 2018 May 29;9(41):26543-26555. Epub 2018 May 29.

Justus-Liebig University, Department of Pediatric Hematology and Oncology, Giessen, Germany.

( fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating DNA copies in the plasma fraction of 37 blood samples. With genomic fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.
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http://dx.doi.org/10.18632/oncotarget.25489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995187PMC
May 2018

Immune Response against ALK in Children with ALK-Positive Anaplastic Large Cell Lymphoma.

Cancers (Basel) 2018 Apr 10;10(4). Epub 2018 Apr 10.

Department of Pediatric Hematology and Oncology, Justus-Liebig University, D-35392 Giessen, Germany.

Patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount a humoral and cellular immune response against ALK. More than 90% of children and adolescents with ALK-positive ALCL have detectable anti-ALK antibodies in serum or plasma, and the antibody titer inversely correlates with the risk of relapse. ALK-specific CD8 and CD4 T cell responses have been described in patients with ALK-positive ALCL. Vaccination with ALK DNA led to protection against lymphoma growth in a murine model. Collectively, these data suggest that the ALK-specific immune response is involved in the control of the disease. The characteristics of the humoral and cellular immune response against ALK as well as tumor immune escape mechanisms have been increasingly investigated. However, tumor and host factors contributing to the individual immune response against ALK are still largely unknown. Depending on the individual strength of the immune response and its determinants, individualized immunological approaches might be appropriate for the consolidation of ALCL patients. Strategies such as ALK vaccination could be effective for those with a pre-existing anti-tumor immunity, while an allogeneic blood stem cell transplantation or check-point inhibition could be effective for others.
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http://dx.doi.org/10.3390/cancers10040114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923369PMC
April 2018

The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.

Leukemia 2018 09 28;32(9):1994-2007. Epub 2018 Mar 28.

Max-Delbrück-Center for Molecular Medicine, 13125, Berlin, Germany.

Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK and ALK anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17-, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3.
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http://dx.doi.org/10.1038/s41375-018-0045-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127090PMC
September 2018

Blood cytokine concentrations in pediatric patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

Haematologica 2018 03 14;103(3):477-485. Epub 2017 Dec 14.

NHL-BFM Study Center, Department of Pediatric Hematology and Oncology, Justus-Liebig University, Giessen.

Patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma often present with B-symptoms or hemophagocytosis and generate an anti-tumor immune response. Specific serum cytokine levels or profiles may reflect the tumor burden, non-specific immune stimulation by the tumor or differences in the strength of the patients' anti-lymphoma immunity. We systematically correlated pretreatment concentrations of 25 cytokines with clinical and biological characteristics in a well-characterized cohort of 119 uniformly treated pediatric patients with anaplastic large cell lymphoma. Fifteen patients with anaplastic large cell lymphoma in remission and 11 patients with low-stage B-cell lymphoma served as controls. Concentrations of interleukin-9, interleukin-10, interleukin-17a, hepatocyte growth factor, soluble interleukin-2 receptor, and soluble CD30 were significantly higher in initial sera of patients than in the sera of subjects from both control groups, indicating an anaplastic large cell lymphoma-type cytokine signature. The levels of interleukin-6, interferon-γ, interferon γ-induced protein, and soluble interleukin-2 receptor correlated with the stage, initial general condition, minimal disseminated disease, anaplastic lymphoma kinase-antibody titers, and the risk of relapse among patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Only interleukin-6 showed an independent prognostic value in multivariate analyses. Pretreatment cytokine profiles in patients with anaplastic large cell lymphoma reflect a tumor signature as well as tumor burden and also differences in the strength of the patients' immune response.
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http://dx.doi.org/10.3324/haematol.2017.177972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830391PMC
March 2018

Course of anti-ALK antibody titres during chemotherapy in children with anaplastic large cell lymphoma.

Br J Haematol 2018 09 31;182(5):733-735. Epub 2017 Aug 31.

NHL-BFM Study Centre and Department of Paediatric Haematology and Oncology, Justus-Liebig-University, Giessen, Germany.

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http://dx.doi.org/10.1111/bjh.14864DOI Listing
September 2018

Anti-ALK Antibodies in Patients with ALK-Positive Malignancies Not Expressing NPM-ALK.

J Cancer 2016 30;7(11):1383-7. Epub 2016 Jun 30.

1. NHL-BFM Study Centre and Department of Paediatric Haematology and Oncology, Justus-Liebig-University, Giessen, Germany.

Patients with Nucleophosmin (NPM)- Anaplastic Lymphoma Kinase (ALK) fusion positive Anaplastic Large Cell Lymphoma produce autoantibodies against ALK indicative of an immune response against epitopes of the chimeric fusion protein. We asked whether ALK-expression in other malignancies induces specific antibodies. Antibodies against ALK were detected in sera of one of 50 analysed ALK-expressing neuroblastoma patients, 13 of 21 ALK positive non-small cell lung carcinoma (NSCLC) patients, 13 of 22 ALK translocation-positive, but NPM-ALK-negative lymphoma patients and one of one ALK-positive rhabdomyosarcoma patient, but not in 20 healthy adults. These data suggest that boosting a pre-existent anti-ALK immune response may be more feasible for patients with ALK-positive NSCLC, lymphomas and rhabdomyosarcomas than for tumours expressing wild-type ALK.
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http://dx.doi.org/10.7150/jca.15238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964121PMC
July 2016

Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.

Ann Hematol 2016 Sep 4;95(9):1503-12. Epub 2016 Jul 4.

Pediatric Hematology and Oncology, NHL-BFM Study Center, Justus Liebig University Giessen, Giessen, Germany.

Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab.
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http://dx.doi.org/10.1007/s00277-016-2731-xDOI Listing
September 2016

Non-Hodgkin Lymphoma in Children and Adolescents: Progress Through Effective Collaboration, Current Knowledge, and Challenges Ahead.

J Clin Oncol 2015 Sep 24;33(27):2963-74. Epub 2015 Aug 24.

Véronique Minard-Colin, Laurence Brugières, Anne Auperin, Marie-Cécile Le Deley, and Catherine Patte, Institut Gustave Roussy, Villejuif; Martine Raphael, Centre National de la Recherche Scientifique UMR 8126, Université Paris Sud; Elizabeth Macintyre, Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, and Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris; Laurence Lamant, Institut Universitaire du Cancer Toulouse Oncopole and Université Paul-Sabatier, Toulouse, France; Alfred Reiter, Wilhelm Woessmann, and Christine Damm-Welk, Justus-Liebig-University Giessen, Giessen; Birgit Burkhardt, Children University Hospital, Münster; Martin Zimmerman, Medizinische Hochschule, Hannover; Wolfram Klapper, Christian-Albrechts-University Kiel, Kiel, Germany; Mitchell S. Cairo, New York Medical College, Valhalla, NY; Thomas G. Gross, National Cancer Institute, Bethesda, MD; John T. Sandlund, St Jude Children's Research Hospital and University of Tennessee Health Science Center, College of Medicine, Memphis, TN; Sherrie L. Perkins, University of Utah Health Sciences, Salt Lake City, UT; Denise Williams, Cambridge University Hospitals Foundation Trust, Cambridge, United Kingdom; Marta Pillon and Angelo Rosolen, University of Padova, Padova; Lara Mussolin, Istituto di Ricerca Pediatrico-Fondazione Cittàdella Speranza and University of Padua, Padua, Italy; Keizo Horibe, National Hospital Organization Nagoya Medical Center, Nagoya, Japan; and Hélène A. Poirel, Center for Human Genetics, Cliniques Universitaires Saint-Luc-Université Catholique de Louvain, Belgium, Brussels.

Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse.
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http://dx.doi.org/10.1200/JCO.2014.59.5827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979194PMC
September 2015

Prognostic factors in paediatric anaplastic large cell lymphoma: role of ALK.

Front Biosci (Schol Ed) 2015 Jun 1;7:205-16. Epub 2015 Jun 1.

Justus-Liebig-University, Department of Pediatric Hematology and Oncology, Feulgenstr. 12, D-35392 Giessen, Germany,,

Event-free survival of children and adolescents with ALK-positive anaplastic large cell lymphoma (ALCL) reaches 65-75% with current chemotherapy regimen. Risk stratification of children with ALCL was, until now, based on clinical parameters. More recently, pathological and biological risk factors have been described in trials applying BFM-type chemotherapy. Histological subtypes containing small-cell or lymphohistiocytic components indicate a high risk of failure. Minimal disseminated disease (MDD) detected by qualitative RT-PCR for NPM-ALK in bone marrow or blood is associated with a relapse risk of 50%. Quantification of MDD and persistent minimal residual disease (MRD) characterize very high risk patients. Serum ALK-autoantibody titres inversely correlate with relapse risk. The combination of MDD and ALK-antibody titre separates both low and very high risk patients from those with standard risk. In relapse, the time of relapse/progression, central nervous system and bone marrow involvement are major risk factors. In conclusion, MDD, MRD, ALK-antibody titres and histological subtype are strong biological risk factors in childhood ALCL. The combination of MDD and ALK-antibody titre may serve for patient stratification in upcoming clinical trials.
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http://dx.doi.org/10.2741/S434DOI Listing
June 2015

Multiplex ligation-dependent probe amplification validates LOH6q analyses and enhances insight into chromosome 6q aberrations in pediatric T-cell lymphoblastic leukemia and lymphoma.

Leuk Lymphoma 2015 Jun 19;56(6):1884-7. Epub 2014 Nov 19.

NHL-BFM Study Center and Department of Pediatric Hematology and Oncology, Justus Liebig University Giessen , Giessen , Germany.

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http://dx.doi.org/10.3109/10428194.2014.976820DOI Listing
June 2015

Recurrent RHOA mutations in pediatric Burkitt lymphoma treated according to the NHL-BFM protocols.

Genes Chromosomes Cancer 2014 Nov 8;53(11):911-6. Epub 2014 Jul 8.

Department of Pediatric Hematology and Oncology, University Hospital Giessen, Giessen, Germany.

Burkitt lymphoma (BL) is the most frequent B-cell lymphoma in childhood. Genetically, it is characterized by the presence of an IG-MYC translocation which is supposed to be an initiating but not sufficient event in Burkitt lymphomagenesis. In a recent whole-genome sequencing study of four cases, we showed that the gene encoding the ras homolog family member A (RHOA) is recurrently mutated in pediatric BL. Here, we analyzed RHOA by Sanger sequencing in a cohort of 101 pediatric B-cell lymphoma patients treated according to Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster (NHL-BFM) study protocols. Among the 78 BLs in this series, an additional five had RHOA mutations resulting in a total incidence of 7/82 (8.5%) with c.14G>A (p.R5Q) being present in three cases. Modeling the mutational effect suggests that most of them inactivate the RHOA protein. Thus, deregulation of RHOA by mutation is a recurrent event in Burkitt lymphomagenesis in children.
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http://dx.doi.org/10.1002/gcc.22202DOI Listing
November 2014

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.

Blood 2014 Feb 7;123(8):1187-98. Epub 2014 Jan 7.

Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany;

The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.
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http://dx.doi.org/10.1182/blood-2013-06-507996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931189PMC
February 2014

Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma.

Blood 2014 Jan 2;123(3):334-7. Epub 2013 Dec 2.

Non-Hodgkin Lymphoma-Berlin-Frankfurt-Münster Study Center, Department of Pediatric Hematology and Oncology, Justus-Liebig University, Giessen, Germany;

Detection of minimal disseminated disease (MDD) at diagnosis correlates with relapse risk in children with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL). We investigated whether minimal residual disease (MRD) positivity by qualitative reverse-transcriptase polymerase chain reaction (RT-PCR) for Nucleophosmin (NPM)-ALK during treatment identifies patients at the highest relapse risk. Blood and/or bone marrow of 180 patients with NPM-ALK-positive ALCL treated with Berlin-Frankfurt-Münster-type protocols were screened for NPM-ALK transcripts at diagnosis; 103 were found to be MDD-positive. MRD before the second therapy course could be evaluated in 52 MDD-positive patients. MRD positivity correlated with uncommon histology. The cumulative incidence of relapses (CIR) of 26 MDD-positive/MRD-positive patients (81% ± 8%) was significantly higher than the CIR of 26 MDD-positive/MRD-negative (31% ± 9%) and 77 MDD-negative patients (15% ± 5%) (P < .001). Five-year survival of MDD-negative and MDD-positive/MRD-negative patients was 91% ± 3% and 92% ± 5%, respectively, compared with 65% ± 9% of MDD-positive/MRD-positive patients (P < .001). Early evaluation of MRD in NPM-ALK-positive ALCL identifies patients with a very high relapse risk and inferior survival.
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http://dx.doi.org/10.1182/blood-2013-09-526202DOI Listing
January 2014

Expression of CD8 is associated with non-common type morphology and outcome in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

Haematologica 2013 Oct 28;98(10):1547-53. Epub 2013 May 28.

Anaplastic lymphoma kinase-positive anaplastic large T-cell lymphoma is characterized by morphological variability. Morphological variants (non-common subtype) are associated with a poor outcome. They display abundant reactive bystander cells admixed with the lymphoma cells. So far, the difficulty in distinguishing lymphoma cells from bystander cells by visual inspection has prevented detailed and reliable immunophenotypic analysis using conventional immunohistochemistry. To overcome these limitations, we analyzed 124 cases of pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma treated within clinical trials using immunofluorescence multi-staining and digital image analysis combining antibodies against anaplastic lymphoma kinase to specifically identify lymphoma cells with antibodies against CD30, CD3, CD5, CD8, Ki67 and phosphorylated STAT3. Non-common type anaplastic lymphoma kinase-positive anaplastic large cell lymphomas express CD8 more frequently than common type anaplastic lymphoma kinase-positive anaplastic large cell lymphomas (35.4% and 5.6%, respectively; P=0.0002). CD8 expression was associated with a poorer outcome. Importantly, in a multivariate analysis including clinical risk factors, histological subtype and CD8 expression, CD8-positivity proved to be an independent prognostic predictor of worse outcome (hazard ratio for survival 3.38, P=0.042).
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http://dx.doi.org/10.3324/haematol.2013.085837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789459PMC
October 2013

The CBFA2T3/ACSF3 locus is recurrently involved in IGH chromosomal translocation t(14;16)(q32;q24) in pediatric B-cell lymphoma with germinal center phenotype.

Genes Chromosomes Cancer 2012 Apr;51(4):338-43

Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University, Kiel, Germany.

Translocations involving immunoglobulin (IG) loci are the hallmarks of several subtypes of B-cell lymphoma. Common to these translocations is that cellular proto-oncogenes come under the influence of IG regulatory elements leading to deregulated expression. In case of a breakpoint in the IGH switch region, oncogene activation can take place on both derivative chromosomes, which means that in principle one translocation can result in concurrent activation of two genes. By fluorescence in situ hybridization (FISH), we identified a case of leukemic B-cell lymphoma in a child with an IGH break and unknown partner. Subsequent long-distance inverse PCR revealed fusion of IGH Sl in 14q32 and the 50 region of CBFA2T3 in 16q24.3, suggesting presence of the t(14;16)(q32;q24.3). Candidate oncogenes targeted through this translocation are CBFA2T3 and ACSF3, which could be activated on der(16) and der(14), respectively. FISH screening of a population-based cohort of B-cell lymphomas from a prospective trial for the treatment of lymphoma in childhood (BFM-NHL) identified additionally a follicular lymphoma Grade 3/diffuse large B-cell lymphoma with IGH-CBFA2T3/ACSF3 juxtaposition. Both lymphomas shared expression of CD10 and CD20 in the absence of TdT, suggesting a germinal center (GC) B-cell origin. Our data indicate that the CBFA2T3/ACSF3 locus is a novel recurrent oncogenic target of IGH translocations, which might contribute to the pathogenesis of pediatric GC-derived B-cell lymphoma.
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http://dx.doi.org/10.1002/gcc.21919DOI Listing
April 2012

Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas.

PLoS One 2011 Apr 8;6(4):e18436. Epub 2011 Apr 8.

Hematology and Oncology Division, Weill Cornell Medical College, Cornell University, New York, New York, United States of America.

ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018436PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072987PMC
April 2011

Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk.

Blood 2010 Apr 25;115(16):3314-9. Epub 2010 Feb 25.

University of Oxford, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK.

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) constitutes an ideal model disease to study tumor-specific immune responses. All the tumor cells express oncogenic ALK resulting from a chromosomal translocation involved in lymphomagenesis. Although antibodies and T-cell responses to ALK have previously been detected in ALK-positive ALCL patients, their prognostic significance is unknown. We investigated a large cohort of uniformly treated ALK-positive pediatric ALCL patients to ascertain whether the titers of preexisting ALK autoantibodies correlated with clinical and histologic characteristics, tumor dissemination, and patient outcome. ALK autoantibodies were analyzed in pretherapeutic serum samples from 95 patients enrolled into 2 therapy studies between 1996 and 2007. ALK autoantibodies were detected in 87/95 patients. The titers inversely correlated with stage and amount of circulating tumor cells. High antibody titers correlated with significantly lower cumulative incidence of relapses (CI-R): titers > or = 1/60 750, n = 29, CI-R 11% +/- 6%; titers 1/2025-< 1/60 750, n = 39, CI-R 31% +/- 8%; and titers 0-< or = 1/750, n = 27, CI-R of 63% +/- 10% (P < .001). Our results provide the first clinical evidence that a robust preexisting immune response to an oncoantigen resulting from an oncogenic chromosomal translocation inhibits lymphoma dissemination and decreases the risk of relapse.
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http://dx.doi.org/10.1182/blood-2009-11-251892DOI Listing
April 2010

Distribution of NPM1-ALK and X-ALK fusion transcripts in paediatric anaplastic large cell lymphoma: a molecular-histological correlation.

Br J Haematol 2009 Aug 26;146(3):306-9. Epub 2009 May 26.

Department of Paediatric Haematology and Oncology, Justus-Liebig University, Giessen, Germany.

Anaplastic large cell lymphomas (ALCL) in children express anaplastic lymphoma kinase (ALK) fusion genes, most commonly NPM1-ALK. The distribution of X-ALK among 66 childhood ALCLs was analysed. One ALCL was ALK-negative. Reverse transcription polymerase chain reaction detected NPM1-ALK in 58 tumours, all showing nuclear and cytoplasmic ALK staining. The remaining seven ALCL stained for ALK in the cytoplasm only: two expressed TPM3-ALK, one ATIC-ALK, one MYH9-ALK; three no TPM3-, TFG-, ATIC-, CLTC- or MYH9-ALK. Almost 90% of paediatric ALK-positive ALCLs express NPM1-ALK. There was complete concordance between ALK staining pattern and the presence of a typical/variant ALK fusion partner.
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http://dx.doi.org/10.1111/j.1365-2141.2009.07754.xDOI Listing
August 2009

Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact.

Leuk Lymphoma 2008 Mar;49(3):451-61

Department of Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany.

Deletions on chromosome 6q are frequently reported in hematological malignancies. However, their biological or prognostic impact has not yet been clarified. This study analyzed loss of heterozygosity (LOH) at chromosome 6q and compared the LOH findings in pediatric precursor T lymphoblastic lymphoma (T-LBL) with the LOH findings in precursor-T lymphoblastic leukemia (T-ALL). For LOH analyses, a set of 25 microsatellite-markers on 6q14-q24 were examined. All patients were treated uniformly according to ALL-BFM-type treatment-strategy. A total of 1671 markers were successfully analyzed from 108 T-LBL patients. LOH was detected in 21 T-LBL patients. There was clear association between LOH at 6q and an increased risk of relapse. In comparison, 3109 markers were successfully analyzed from 127 T-ALL-patients. LOH was detected in 16 patients, but was not associated with increased relapse-rate. The localization of the common LOH regions identified for T-LBL and T-ALL samples did not overlap. Therefore patterns of LOH at 6q and the prognostic impact of LOH differ between T-ALL and T-LBL. These results hint at biologic differences between the two diseases.
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http://dx.doi.org/10.1080/10428190701824551DOI Listing
March 2008

Flow cytometric detection of circulating tumour cells in nucleophosmin/anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: comparison with quantitative polymerase chain reaction.

Br J Haematol 2007 Aug 29;138(4):459-66. Epub 2007 Jun 29.

Department of Paediatric Haematology and Oncology, Justus-Liebig University, Giessen, Germany.

Quantification of occult circulating tumour cells in blood or bone marrow (BM) enables the identification of patients with a high risk for relapse in nucleophosmin/anaplastic lymphoma kinase (NPM-ALK)-positive anaplastic large cell lymphoma (ALCL). We have developed a flow cytometric (FCM) assay to quantify the rare ALK- and CD30-positive ALCL cells. When ALCL cells were admixed with normal peripheral blood or BM, ALK- and CD30-positive cells could be detected above background level at an added concentration of 10(-5) for all three cell lines tested. Sensitivity and costs of the assay were compared with quantitative real-time polymerase chain reaction (PCR) for NPM-ALK. The results of the FCM assay and quantitative PCR for NPM-ALK correlated. The sensitivity of the PCR exceeded that of the FCM by at least one log. Quantitative PCR was more time-consuming and expensive than FCM. Both methods were compared on BM or blood samples from 11 ALCL patients. FCM using antibodies against ALK and CD30 can sensitively and specifically detect the circulating ALCL cells in BM or blood. This method needs to be tested in a larger cohort of patients to determine whether it has sufficient sensitivity to be used as a substitute for quantitative PCR.
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http://dx.doi.org/10.1111/j.1365-2141.2007.06672.xDOI Listing
August 2007

Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma.

Blood 2007 Jul 28;110(2):670-7. Epub 2007 Mar 28.

Justus-Liebig-University, Department of Pediatric Hematology and Oncology, Giessen, Germany.

Clinical and histopathological characteristics have limited prognostic value for children with anaplastic large-cell lymphoma (ALCL). We evaluated the presence, extent, and prognostic impact of circulating tumor cells in bone marrow (BM) and peripheral blood (PB) of children and adolescents with NPM-ALK-positive ALCL at diagnosis using qualitative and quantitative polymerase chain reaction (PCR) for NPM-ALK. Numbers of NPM-ALK transcripts were normalized to 10(4) copies ABL (NCNs). BM was analyzed from 80 patients and PB from 52. BM was positive for NPM-ALK in 47.5% of patients, and positivity was significantly correlated with clinical stage, mediastinal or visceral involvement, microscopic BM involvement, and histologic subtype. Qualitative and quantitative PCR results in BM and PB strongly correlated. BM PCR was associated with the cumulative incidence of relapses (CI-Rs): CI-R was 50% +/- 10% for 38 PCR-positive and 15% +/- 7% for 42 PCR-negative patients (P < .001). Sixteen patients with more than 10 NCNs NPM-ALK in BM had a CI-R of 71% +/- 14% compared with a CI-R of 18% +/- 6% for 59 patients with 10 or fewer NCNs (P < .001). PB PCR results led to a similar grouping. Thus, quantitative PCR in BM or PB allows identification of 20% of patients experiencing 60% of all relapses with an event-free survival of 20%.
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http://dx.doi.org/10.1182/blood-2007-02-066852DOI Listing
July 2007

RNA interference: new mechanisms for targeted treatment?

Rev Clin Exp Hematol 2003 Sep;7(3):270-91

Dept. of Pediatric Hematology and Oncology, Justus-Liebig-University, 35385 Giessen, Germany.

Nucleic acid-based sequence-specific therapeutic intervention offers the potential for treatment of particular cancers without side effects. RNA interference (RNAi) induced by small interfering RNA (siRNA) (19-21 bp) is a normal cellular mechanism leading to highly specific and extraordinarily efficient degradation of the corresponding mRNA. The mechanism of RNAi as well as strategies for the design and delivery of siRNA are described. The growing role of RNAi in target validation for cancer-specific genetic aberrations is discussed. We attempt an early assessment of the potential for using RNAi technologies to treat cancer directly, especially hematologic malignancies. Promising targets for specific gene silencing in hematologic oncology include oncogenic fusion proteins and oncogenes activated by point mutations. Potency and specificity of gene silencing are the major advantages of the new RNAi technology over other nucleic acid-based gene targeting approaches. Crucial questions for pharmaceutical interventions remain. Advances in the areas of delivery, systemic spreading and duration of the silencing effect are necessary before the methodology can enter clinical oncology.
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September 2003

Targeting oncogenic fusion genes in leukemias and lymphomas by RNA interference.

Semin Cancer Biol 2003 Aug;13(4):283-92

Pediatric Hematology & Oncology, Children's University Hospital Giessen, Feulgenstr. 12, 35392 Giessen, Germany.

Leukemias and lymphomas are often characterized by non-random chromosomal translocations that, at the molecular level, induce the activation of specific oncogenes or create novel chimeric genes. They have frequently been regarded as optimal targets for gene-silencing approaches because of the large body of evidence that these single abnormalities directly initiate and maintain the malignant process. Herein, we discuss RNA interference (RNAi)-based approaches for targeting the fusion sites of chromosomal translocations as a future treatment option in leukemias and lymphomas.
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http://dx.doi.org/10.1016/s1044-579x(03)00042-7DOI Listing
August 2003
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