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Markus Müschen

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https://www.readbyqxmd.com/read/28655536/b-cell-identity-as-a-metabolic-barrier-against-malignant-transformation
#1
REVIEW
Lai N Chan, Markus Müschen
B-lineage and myeloid leukemia cells are often transformed by the same oncogenes, but have different biological and clinical characteristics. Although B-lineage acute lymphoblastic leukemia (B-ALL) cells are characterized by a state of chronic energy deficit, myeloid leukemia cells show abundant energy reserve. Interestingly, fasting has been demonstrated to inhibit selectively the development of B-ALL but not myeloid leukemia, further suggesting that lineage identity may be linked to divergent metabolic states in hematopoietic malignancies...
June 24, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28630052/infection-exposure-promotes-etv6-runx1-precursor-b-cell-leukemia-via-impaired-h3k4-demethylases
#2
Guillermo Rodríguez-Hernández, Julia Hauer, Alberto Martín-Lorenzo, Daniel Schäfer, Christoph Bartenhagen, Idoia García-Ramírez, Franziska Auer, Ines Gonzalez-Herrero, Lucia Ruiz-Roca, Michael Gombert, Vera Okpanyi, Ute Fischer, Cai Chen, Martin Dugas, Sanil Bhatia, René M Linka, Marta Garcia-Suquia, María V Rascón-Trincado, Angel Garcia-Sanchez, Oscar Blanco, Maria Begona Garcia-Cenador, Francisco Javier Garcia-Criado, César Cobaleda, Diego Alonso-López, Javier De Las Rivas, Markus Müschen, Carolina Vicente-Dueñas, Isidro Sánchez-García, Arndt Borkhardt
<p>ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/peripheral cells (HSC/PC) and postnatal infections for human-like pB-ALL...
June 19, 2017: Cancer Research
https://www.readbyqxmd.com/read/28566433/mtorc1-inhibition-induces-resistance-to-methotrexate-and-6-mercaptopurine-in-ph-and-ph-like-b-all
#3
Thanh-Trang T Vo, Jong-Hoon S Lee, Duc Nguyen, Brandon Lui, William Pandori, Andrew Khaw, Sharmila Mallya, Mengrou Lu, Markus Müschen, Marina Konopleva, David A Fruman
Elevated activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph(+) and Ph-like B-ALL models...
May 31, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28481221/gene-expression-and-mutation-guided-synthetic-lethality-eradicates-proliferating-and-quiescent-leukemia-cells
#4
Margaret Nieborowska-Skorska, Katherine Sullivan, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Grazyna Hoser, Silvia Maifrede, Esteban Martinez, Daniela Di Marcantonio, Elisabeth Bolton-Gillespie, Kimberly Cramer-Morales, Jaewong Lee, Min Li, Artur Slupianek, Daniel Gritsyuk, Sabine Cerny-Reiterer, Ilona Seferynska, Tomasz Stoklosa, Lars Bullinger, Huaqing Zhao, Vera Gorbunova, Katarzyna Piwocka, Peter Valent, Curt I Civin, Markus Muschen, John E Dick, Jean Cy Wang, Smita Bhatia, Ravi Bhatia, Kolja Eppert, Mark D Minden, Stephen M Sykes, Tomasz Skorski
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...
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28424165/suppression-of-b-cell-development-genes-is-key-to-glucocorticoid-efficacy-in-treatment-of-acute-lymphoblastic-leukemia
#5
Karina A Kruth, Mimi Fang, Dawne N Shelton, Ossama Abu-Halawa, Ryan Mahling, Hongxing Yang, Jonathan S Weissman, Mignon L Loh, Markus Müschen, Sarah K Tasian, Michael C Bassik, Martin Kampmann, Miles A Pufall
Glucocorticoids (GCs), including dexamethasone (dex), are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the GC receptor (GR), a ligand-induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, which pathways affect their regulation, and how resistance arises are not well understood. Here, we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation short hairpin RNA screen to identify GC-regulated "effector" genes that contribute to cell death, as well as genes that affect the sensitivity of B-ALL cells to dex...
June 1, 2017: Blood
https://www.readbyqxmd.com/read/28369050/antagonism-of-b-cell-enhancer-networks-by-stat5-drives-leukemia-and-poor-patient-survival
#6
Casey D S Katerndahl, Lynn M Heltemes-Harris, Mark J L Willette, Christine M Henzler, Seth Frietze, Rendong Yang, Hilde Schjerven, Kevin A T Silverstein, Laura B Ramsey, Gregory Hubbard, Andrew D Wells, Roland P Kuiper, Blanca Scheijen, Frank N van Leeuwen, Markus Müschen, Steven M Kornblau, Michael A Farrar
The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU...
June 2017: Nature Immunology
https://www.readbyqxmd.com/read/28356518/bcl6-promotes-glioma-and-serves-as-a-therapeutic-target
#7
Liang Xu, Ye Chen, Marina Dutra-Clarke, Anand Mayakonda, Masaharu Hazawa, Steve E Savinoff, Ngan Doan, Jonathan W Said, William H Yong, Ashley Watkins, Henry Yang, Ling-Wen Ding, Yan-Yi Jiang, Jeffrey W Tyner, Jianhong Ching, Jean-Paul Kovalik, Vikas Madan, Shing-Leng Chan, Markus Müschen, Joshua J Breunig, De-Chen Lin, H Phillip Koeffler
ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28202506/recurrent-patterns-of-dna-copy-number-alterations-in-tumors-reflect-metabolic-selection-pressures
#8
Nicholas A Graham, Aspram Minasyan, Anastasia Lomova, Ashley Cass, Nikolas G Balanis, Michael Friedman, Shawna Chan, Sophie Zhao, Adrian Delgado, James Go, Lillie Beck, Christian Hurtz, Carina Ng, Rong Qiao, Johanna Ten Hoeve, Nicolaos Palaskas, Hong Wu, Markus Müschen, Asha S Multani, Elisa Port, Steven M Larson, Nikolaus Schultz, Daniel Braas, Heather R Christofk, Ingo K Mellinghoff, Thomas G Graeber
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including (18)F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation...
February 15, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28199841/lineage-specific-genes-are-prominent-dna-damage-hotspots-during-leukemic-transformation-of-b-cell-precursors
#9
Bryant Boulianne, Mark E Robinson, Philippa C May, Leandro Castellano, Kevin Blighe, Jennifer Thomas, Alistair Reid, Markus Müschen, Jane F Apperley, Justin Stebbing, Niklas Feldhahn
In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B cell precursors expressing leukemia-inducing oncogenes by ChIP-seq. We identified more than 1,000 sensitive regions, of which B lineage-specific genes constitute the most prominent targets. Identified hotspots at B lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells...
February 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28192788/metabolic-gatekeeper-function-of-b-lymphoid-transcription-factors
#10
Lai N Chan, Zhengshan Chen, Daniel Braas, Jae-Woong Lee, Gang Xiao, Huimin Geng, Kadriye Nehir Cosgun, Christian Hurtz, Seyedmehdi Shojaee, Valeria Cazzaniga, Hilde Schjerven, Thomas Ernst, Andreas Hochhaus, Steven M Kornblau, Marina Konopleva, Miles A Pufall, Giovanni Cazzaniga, Grace J Liu, Thomas A Milne, H Phillip Koeffler, Theodora S Ross, Isidro Sánchez-García, Arndt Borkhardt, Keith R Yamamoto, Ross A Dickins, Thomas G Graeber, Markus Müschen
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply...
February 23, 2017: Nature
https://www.readbyqxmd.com/read/28031181/ibrutinib-inhibits-pre-bcr-b-cell-acute-lymphoblastic-leukemia-progression-by-targeting-btk-and-blk
#11
Ekaterina Kim, Christian Hurtz, Stefan Koehrer, Zhiqiang Wang, Sriram Balasubramanian, Betty Y Chang, Markus Müschen, R Eric Davis, Jan A Burger
Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR(+) B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR(+) ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations...
March 2, 2017: Blood
https://www.readbyqxmd.com/read/27479034/the-public-repository-of-xenografts-enables-discovery-and-randomized-phase-ii-like-trials-in-mice
#12
Elizabeth C Townsend, Mark A Murakami, Alexandra Christodoulou, Amanda L Christie, Johannes Köster, Tiffany A DeSouza, Elizabeth A Morgan, Scott P Kallgren, Huiyun Liu, Shuo-Chieh Wu, Olivia Plana, Joan Montero, Kristen E Stevenson, Prakash Rao, Raga Vadhi, Michael Andreeff, Philippe Armand, Karen K Ballen, Patrizia Barzaghi-Rinaudo, Sarah Cahill, Rachael A Clark, Vesselina G Cooke, Matthew S Davids, Daniel J DeAngelo, David M Dorfman, Hilary Eaton, Benjamin L Ebert, Julia Etchin, Brant Firestone, David C Fisher, Arnold S Freedman, Ilene A Galinsky, Hui Gao, Jacqueline S Garcia, Francine Garnache-Ottou, Timothy A Graubert, Alejandro Gutierrez, Ensar Halilovic, Marian H Harris, Zachary T Herbert, Steven M Horwitz, Giorgio Inghirami, Andrew M Intlekofer, Moriko Ito, Shai Izraeli, Eric D Jacobsen, Caron A Jacobson, Sébastien Jeay, Irmela Jeremias, Michelle A Kelliher, Raphael Koch, Marina Konopleva, Nadja Kopp, Steven M Kornblau, Andrew L Kung, Thomas S Kupper, Nicole R LeBoeuf, Ann S LaCasce, Emma Lees, Loretta S Li, A Thomas Look, Masato Murakami, Markus Muschen, Donna Neuberg, Samuel Y Ng, Oreofe O Odejide, Stuart H Orkin, Rachel R Paquette, Andrew E Place, Justine E Roderick, Jeremy A Ryan, Stephen E Sallan, Brent Shoji, Lewis B Silverman, Robert J Soiffer, David P Steensma, Kimberly Stegmaier, Richard M Stone, Jerome Tamburini, Aaron R Thorner, Paul van Hummelen, Martha Wadleigh, Marion Wiesmann, Andrew P Weng, Jens U Wuerthner, David A Williams, Bruce M Wollison, Andrew A Lane, Anthony Letai, Monica M Bertagnolli, Jerome Ritz, Myles Brown, Henry Long, Jon C Aster, Margaret A Shipp, James D Griffin, David M Weinstock
No abstract text is available yet for this article.
July 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27071778/effects-of-pharmacological-and-genetic-disruption-of-cxcr4-chemokine-receptor-function-in-b-cell-acute-lymphoblastic-leukaemia
#13
Shubhchintan Randhawa, Byung S Cho, Dipanjan Ghosh, Mariela Sivina, Stefan Koehrer, Markus Müschen, Amnon Peled, Richard E Davis, Marina Konopleva, Jan A Burger
B cell acute lymphoblastic leukaemia (B-ALL) cells express high levels of CXCR4 chemokine receptors for homing and retention within the marrow microenvironment. Bone marrow stromal cells (BMSC) secrete CXCL12, the ligand for CXCR4, and protect B-ALL cells from cytotoxic drugs. Therefore, the therapeutic use of CXCR4 antagonists has been proposed to disrupt cross talk between B-ALL cells and the protective stroma. Because CXCR4 antagonists can have activating agonistic function, we compared the genetic and pharmacological deletion of CXCR4 in B-ALL cells, using CRISPR-Cas9 gene editing and CXCR4 antagonists that are in clinical use (plerixafor, BKT140)...
August 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27070704/the-public-repository-of-xenografts-enables-discovery-and-randomized-phase-ii-like-trials-in-mice
#14
Elizabeth C Townsend, Mark A Murakami, Alexandra Christodoulou, Amanda L Christie, Johannes Köster, Tiffany A DeSouza, Elizabeth A Morgan, Scott P Kallgren, Huiyun Liu, Shuo-Chieh Wu, Olivia Plana, Joan Montero, Kristen E Stevenson, Prakash Rao, Raga Vadhi, Michael Andreeff, Philippe Armand, Karen K Ballen, Patrizia Barzaghi-Rinaudo, Sarah Cahill, Rachael A Clark, Vesselina G Cooke, Matthew S Davids, Daniel J DeAngelo, David M Dorfman, Hilary Eaton, Benjamin L Ebert, Julia Etchin, Brant Firestone, David C Fisher, Arnold S Freedman, Ilene A Galinsky, Hui Gao, Jacqueline S Garcia, Francine Garnache-Ottou, Timothy A Graubert, Alejandro Gutierrez, Ensar Halilovic, Marian H Harris, Zachary T Herbert, Steven M Horwitz, Giorgio Inghirami, Andrew M Intlekofer, Moriko Ito, Shai Izraeli, Eric D Jacobsen, Caron A Jacobson, Sébastien Jeay, Irmela Jeremias, Michelle A Kelliher, Raphael Koch, Marina Konopleva, Nadja Kopp, Steven M Kornblau, Andrew L Kung, Thomas S Kupper, Nicole R LeBoeuf, Ann S LaCasce, Emma Lees, Loretta S Li, A Thomas Look, Masato Murakami, Markus Muschen, Donna Neuberg, Samuel Y Ng, Oreofe O Odejide, Stuart H Orkin, Rachel R Paquette, Andrew E Place, Justine E Roderick, Jeremy A Ryan, Stephen E Sallan, Brent Shoji, Lewis B Silverman, Robert J Soiffer, David P Steensma, Kimberly Stegmaier, Richard M Stone, Jerome Tamburini, Aaron R Thorner, Paul van Hummelen, Martha Wadleigh, Marion Wiesmann, Andrew P Weng, Jens U Wuerthner, David A Williams, Bruce M Wollison, Andrew A Lane, Anthony Letai, Monica M Bertagnolli, Jerome Ritz, Myles Brown, Henry Long, Jon C Aster, Margaret A Shipp, James D Griffin, David M Weinstock
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...
April 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/26974310/pten-opposes-negative-selection-and-enables-oncogenic-transformation-of-pre-b-cells
#15
Seyedmehdi Shojaee, Lai N Chan, Maike Buchner, Valeria Cazzaniga, Kadriye Nehir Cosgun, Huimin Geng, Yi Hua Qiu, Marcus Dühren von Minden, Thomas Ernst, Andreas Hochhaus, Giovanni Cazzaniga, Ari Melnick, Steven M Kornblau, Thomas G Graeber, Hong Wu, Hassan Jumaa, Markus Müschen
Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia...
April 2016: Nature Medicine
https://www.readbyqxmd.com/read/26958840/corrigendum-signalling-thresholds-and-negative-b-cell-selection-in-acute-lymphoblastic-leukaemia
#16
Zhengshan Chen, Seyedmehdi Shojaee, Maike Buchner, Huimin Geng, Jae Woong Lee, Lars Klemm, Björn Titz, Thomas G Graeber, Eugene Park, Ying Xim Tan, Anne Satterthwaite, Elisabeth Paietta, Stephen P Hunger, Cheryl L Willman, Ari Melnick, Mignon L Loh, Jae U Jung, John E Coligan, Silvia Bolland, Tak W Mak, Andre Limnander, Hassan Jumaa, Michael Reth, Arthur Weiss, Clifford A Lowell, Markus Müschen
No abstract text is available yet for this article.
June 2, 2016: Nature
https://www.readbyqxmd.com/read/26934650/inhibition-of-ire1%C3%AE-driven-pro-survival-pathways-is-a-promising-therapeutic-application-in-acute-myeloid-leukemia
#17
Haibo Sun, De-Chen Lin, Xiao Guo, Behzad Kharabi Masouleh, Sigal Gery, Qi Cao, Serhan Alkan, Takayuki Ikezoe, Chie Akiba, Ronald Paquette, Wenwen Chien, Carsten Müller-Tidow, Yang Jing, Konstantin Agelopoulos, Markus Müschen, H Phillip Koeffler
Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1α-XBP1 pathway, a key branch of the UPR, is activated in many cancers. Here, we show that the expression of both mature and spliced forms of XBP1 (XBP1s) is up-regulated in acute myeloid leukemia (AML) cell lines and AML patient samples. IRE1α RNase inhibitors [MKC-3946, 2-hydroxy-1-naphthaldehyde (HNA), STF-083010 and toyocamycin] blocked XBP1 mRNA splicing and exhibited cytotoxicity against AML cells...
April 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/26864341/normal-abl1-is-a-tumor-suppressor-and-therapeutic-target-in-human-and-mouse-leukemias-expressing-oncogenic-abl1-kinases
#18
Yashodhara Dasgupta, Mateusz Koptyra, Grazyna Hoser, Kanchan Kantekure, Darshan Roy, Barbara Gornicka, Margaret Nieborowska-Skorska, Elisabeth Bolton-Gillespie, Sabine Cerny-Reiterer, Markus Müschen, Peter Valent, Mariusz A Wasik, Christine Richardson, Oliver Hantschel, Heiko van der Kuip, Tomasz Stoklosa, Tomasz Skorski
Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells...
April 28, 2016: Blood
https://www.readbyqxmd.com/read/26711339/mll-rearranged-acute-lymphoblastic-leukemias-activate-bcl-2-through-h3k79-methylation-and-are-sensitive-to-the-bcl-2-specific-antagonist-abt-199
#19
Juliana M Benito, Laura Godfrey, Kensuke Kojima, Leah Hogdal, Mark Wunderlich, Huimin Geng, Isabel Marzo, Karine G Harutyunyan, Leonard Golfman, Phillip North, Jon Kerry, Erica Ballabio, Triona Ní Chonghaile, Oscar Gonzalo, Yihua Qiu, Irmela Jeremias, LaKiesha Debose, Eric O'Brien, Helen Ma, Ping Zhou, Rodrigo Jacamo, Eugene Park, Kevin R Coombes, Nianxiang Zhang, Deborah A Thomas, Susan O'Brien, Hagop M Kantarjian, Joel D Leverson, Steven M Kornblau, Michael Andreeff, Markus Müschen, Patrick A Zweidler-McKay, James C Mulloy, Anthony Letai, Thomas A Milne, Marina Konopleva
Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199...
December 29, 2015: Cell Reports
https://www.readbyqxmd.com/read/26637659/infection-and-the-perils-of-b-cell-activation
#20
COMMENT
Mel Greaves, Markus Müschen
Recent studies have linked aberrant B-cell activation in the context of aberrant immune responses to infectious pathogens to malignant transformation and development of leukemia and lymphoma. A new study in this issue demonstrates that common infections can be drivers of clonal evolution of premalignant B-cell precursors toward childhood leukemia.
December 2015: Cancer Discovery
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