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      Ludwig Boltzmann Cluster Oncology (LBC ONC): first 10 years and future perspectives

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          Summary

          In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previous Ludwig Boltzmann Institutes working in the field of hematology and cancer research. The general aim of the LBC ONC is to improve treatment of hematopoietic neoplasms by eradicating cancer-initiating and disease-propagating cells, also known as leukemic stem cells (LSC) in the context of leukemia. In a first phase, the LBC ONC characterized the phenotype and molecular aberration profiles of LSC in various malignancies. The LSC phenotypes were established in acute and chronic myeloid leukemia, in acute lymphoblastic leukemia and in chronic lymphocytic leukemia. In addition, the concept of preleukemic (premalignant) neoplastic stem cells (pre-L-NSC) was coined by the LBC ONC and was tested in myelodysplastic syndromes and myeloproliferative neoplasms. Phenotypic characterization of LSC provided a solid basis for their purification and for the characterization of specific target expression profiles. In a second phase, molecular markers and targets were validated. This second phase is ongoing and should result in the development of new diagnostics parameters and novel, more effective, LSC-eradicating, treatment strategies; however, many issues still remain to be solved, such as sub-clonal evolution, LSC niche interactions, immunologic control of LSC, and LSC resistance. In the forthcoming years, the LBC ONC will concentrate on developing LSC-eradicating strategies, with special focus on LSC resistance, precision medicine and translation of LSC-eradicating concepts into clinical application.

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          Most cited references 75

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          Revised international prognostic scoring system for myelodysplastic syndromes.

          The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.
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            Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft

            Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumor progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumor, a brain metastasis, and a xenograft derived from the primary tumor. The metastasis contained two de novo mutations and a large deletion not present in the primary tumor, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumor mutations, and displayed a mutation enrichment pattern that paralleled the metastasis (16 of 20 genes). Two overlapping large deletions, encompassing CTNNA1, were present in all three tumor samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared to the primary tumor suggest that secondary tumors may arise from a minority of cells within the primary.
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              Identification of cells initiating human melanomas.

              Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.
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                Author and article information

                Contributors
                +43-1-4040060850 , +43-1-4040054880 , +43-1-40300 , peter.valent@meduniwien.ac.at , peter.valent@onc.lbg.ac.at
                Journal
                Wien Klin Wochenschr
                Wien. Klin. Wochenschr
                Wiener Klinische Wochenschrift
                Springer Vienna (Vienna )
                0043-5325
                1613-7671
                13 July 2018
                13 July 2018
                2018
                : 130
                : 17
                : 517-529
                Affiliations
                [1 ]Ludwig Boltzmann Cluster Oncology, Vienna, Austria
                [2 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Internal Medicine I, Division of Hematology & Hemostaseology, , Medical University of Vienna, ; Waehringer Guertel 18–20, Vienna, Austria
                [3 ]ISNI 0000 0000 9686 6466, GRID grid.6583.8, Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, , University of Veterinary Medicine Vienna, ; Vienna, Austria
                [4 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Internal Medicine I, Division of Clinical Oncology, , Medical University of Vienna, ; Vienna, Austria
                [5 ]ISNI 0000 0000 8987 0344, GRID grid.413662.4, Hanusch Hospital, ; Vienna, Austria
                [6 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Radiation Oncology, , Medical University of Vienna, ; Vienna, Austria
                [7 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Laboratory Medicine, , Medical University of Vienna, ; Vienna, Austria
                [8 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Internal Medicine I, Stem Cell Transplantation Unit, , Medical University of Vienna, ; Vienna, Austria
                [9 ]ISNI 0000 0000 9686 6466, GRID grid.6583.8, Department of Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, , University of Veterinary Medicine Vienna, ; Vienna, Austria
                [10 ]ISNI 0000 0000 9686 6466, GRID grid.6583.8, Institute of Laboratory Animal Science, , University of Veterinary Medicine Vienna, ; Vienna, Austria
                [11 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Internal Medicine I, Institute of Cancer Research, , Medical University of Vienna, ; Vienna, Austria
                [12 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Dermatology, , Medical University of Vienna, ; Vienna, Austria
                Article
                1355
                10.1007/s00508-018-1355-7
                6132878
                30006759
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002428, Austrian Science Fund;
                Award ID: F4701 and F4704
                Funded by: Austrian Science Fund (FWF)
                Categories
                Review Article
                Custom metadata
                © Springer-Verlag GmbH Austria, part of Springer Nature 2018

                Medicine

                cancer stem cells, leukemic stem cells, targeted therapy, precision medicine, immunotherapy

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