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Start Over Author "Muschen, Markus" Topic leukemia
3 results on '"Muschen, Markus"'

1. Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells.

Author

Nieborowska-Skorska M, Sullivan K, Dasgupta Y, Podszywalow-Bartnicka P, Hoser G, Maifrede S, Martinez E, Di Marcantonio D, Bolton-Gillespie E, Cramer-Morales K, Lee J, Li M, Slupianek A, Gritsyuk D, Cerny-Reiterer S, Seferynska I, Stoklosa T, Bullinger L, Zhao H, Gorbunova V, Piwocka K, Valent P, Civin CI, Muschen M, Dick JE, Wang JC, Bhatia S, Bhatia R, Eppert K, Minden MD, Sykes SM, and Skorski T

Subjects
Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Cricetinae, DNA Breaks, Double-Stranded, DNA End-Joining Repair, Genes, BRCA1, Genes, BRCA2, Genes, Lethal, Genes, abl, Humans, Leukemia drug therapy, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mouse Embryonic Stem Cells physiology, Phthalazines pharmacology, Piperazines pharmacology, Transcriptome, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Cell Proliferation, Leukemia genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology
Abstract

Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1. DNA-PK-deficient quiescent leukemia cells and BRCA/DNA-PK-deficient proliferating leukemia cells were sensitive to PARP1 inhibitors that were administered alone or in combination with current antileukemic drugs. In conclusion, GEMA-guided targeting of PARP1 resulted in dual cellular synthetic lethality in quiescent and proliferating immature leukemia cells, and is thus a potential approach to eradicate leukemia stem and progenitor cells that are responsible for initiation and manifestation of the disease. Further, an analysis of The Cancer Genome Atlas database indicated that this personalized medicine approach could also be applied to treat numerous solid tumors from individual patients.

Published
2017
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2. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

Author

Townsend EC, Murakami MA, Christodoulou A, Christie AL, Köster J, DeSouza TA, Morgan EA, Kallgren SP, Liu H, Wu SC, Plana O, Montero J, Stevenson KE, Rao P, Vadhi R, Andreeff M, Armand P, Ballen KK, Barzaghi-Rinaudo P, Cahill S, Clark RA, Cooke VG, Davids MS, DeAngelo DJ, Dorfman DM, Eaton H, Ebert BL, Etchin J, Firestone B, Fisher DC, Freedman AS, Galinsky IA, Gao H, Garcia JS, Garnache-Ottou F, Graubert TA, Gutierrez A, Halilovic E, Harris MH, Herbert ZT, Horwitz SM, Inghirami G, Intlekofer AM, Ito M, Izraeli S, Jacobsen ED, Jacobson CA, Jeay S, Jeremias I, Kelliher MA, Koch R, Konopleva M, Kopp N, Kornblau SM, Kung AL, Kupper TS, LeBoeuf NR, LaCasce AS, Lees E, Li LS, Look AT, Murakami M, Muschen M, Neuberg D, Ng SY, Odejide OO, Orkin SH, Paquette RR, Place AE, Roderick JE, Ryan JA, Sallan SE, Shoji B, Silverman LB, Soiffer RJ, Steensma DP, Stegmaier K, Stone RM, Tamburini J, Thorner AR, van Hummelen P, Wadleigh M, Wiesmann M, Weng AP, Wuerthner JU, Williams DA, Wollison BM, Lane AA, Letai A, Bertagnolli MM, Ritz J, Brown M, Long H, Aster JC, Shipp MA, Griffin JD, and Weinstock DM

Subjects
Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Biomarkers, Tumor, Cell Lineage, Female, Gene Expression Profiling, Genes, p53, Humans, Internet, Isoquinolines pharmacology, Isoquinolines therapeutic use, Leukemia metabolism, Leukemia, Experimental drug therapy, Lymphoma metabolism, Male, Mice, Mice, Inbred NOD, Molecular Targeted Therapy, Neoplasm Proteins antagonists & inhibitors, Neoplasm Transplantation, Phenotype, Piperazines pharmacology, Piperazines therapeutic use, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Proteome, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Random Allocation, Randomized Controlled Trials as Topic methods, Research Design, Transcriptome, Heterografts, Leukemia pathology, Lymphoma pathology, Tissue Banks, Xenograft Model Antitumor Assays
Abstract

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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3. Expression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia

Author

Shawn Anderson, Eleanor J. Fraser, Huimin Geng, Zhengshan Chen, James L. Rubenstein, Muschen Markus, Chen Lingjing, Colin Collins, and Ming Lu

Subjects
Immunology, Primary central nervous system lymphoma, BTLA, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Lymphoma, Metastasis, Leukemia, hemic and lymphatic diseases, medicine, Cancer research, B-cell lymphoma, Diffuse large B-cell lymphoma, Comparative genomic hybridization
Abstract

Background. The genetic factors that contribute to dissemination and relapse in aggressive lymphomas and acute lymphoblastic leukemia (ALL) are incompletely defined. We tested the hypothesis that shared molecular pathways contribute to drug resistance and metastasis in three distinct types of lymphoid neoplasms: large B-cell lymphoma, primary central nervous system lymphoma (PCNSL, DLBCL) and ALL. Methods. We used a variety of approaches involving high-resolution array-based comparative genomic hybridization, patient-derived cell lines, murine tumor models, diagnostic tumor specimens, and clinical outcome data sets to interrogate the biological significance of candidate mediators of relapse and CNS metastasis. Results. We first tested the hypothesis that genomic aberrations may contribute to the refractory phenotype in aggressive B-cell lymphoma. To pursue this, we compared DNA copy number aberrations in relapsed large B-cell lymphoma that had metastasized to the brain (3 cases, each isolated by resection) with the genomic changes identified in large B-cell lymphoma at diagnosis (15 cases: 12 PCNSL and 3 nodal lymphomas; all DLBCL). We identified a focal recurrent copy number gain at chromosome 3q encoding two candidate proteins: SIDT1, a mediator of microRNA transport, and BTLA, a member of the CD28 superfamily and modifier of both B-cell receptor signaling as well as T-cell responses. Elevated BTLA transcript and protein expression in relapsed specimens was confirmed. We also demonstrated by immunohistochemistry that tumor cell expression of BTLA but not SIDT1 correlated with short overall survival in an independent set of 40 patients with PCNSL treated uniformly with an immunochemotherapy protocol. Using independent databases of systemic DLBCL (n=203 and 69 respectively, Lenz et al. PNAS 2008; Shaknovich et al. Blood 2010), we determined that expression of both BTLA and SIDT1 were significantly higher in ABC compared to GCB DLBCL (p Conclusions. Taken together these data suggest for the first time that BTLA expression may contribute to metastasis and CNS progression of activated B-cell lymphoma and to resistance in ALL and Ph+ ALL. Our data suggest that BTLA may not only be a useful biomarker in these aggressive neoplasms, but also a potential therapeutic target. Additional studies are needed to deduce the mechanisms by which BTLA contributes to resistance and metastasis in ABC DLBCL and in ALL. Supported by the Leukemia and Lymphoma Society and the National Cancer Institute Disclosures Rubenstein: Celgene: Research Funding; Genentech: Research Funding.

Published
2015
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