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Michelle Le Beau

Jason X Cheng, Li Chen, Yuan Li, Adam Cloe, Ming Yue, Jiangbo Wei, Kenneth A Watanabe, Jamile M Shammo, John Anastasi, Qingxi J Shen, Richard A Larson, Chuan He, Michelle M Le Beau, James W Vardiman
The roles of RNA 5-methylcytosine (RNA:m5 C) and RNA:m5 C methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.1, and with CDK9/P-TEFb to recruit RNA-polymerase-II at nascent RNA, leading to formation of 5-Azacitidine (5-AZA)-sensitive chromatin structure...
March 21, 2018: Nature Communications
Megan E McNerney, Lucy A Godley, Michelle M Le Beau
Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this Review, we discuss recent developments that reframe our understanding of the genetic and environmental aetiology of t-MN. Emerging data are illuminating who is at highest risk of developing t-MN, why t-MN are chemoresistant and how we may use this information to treat and ultimately prevent this lethal disease...
August 24, 2017: Nature Reviews. Cancer
Angela Stoddart, Jianghong Wang, Chunmei Hu, Anthony A Fernald, Elizabeth M Davis, Jason X Cheng, Michelle M Le Beau
There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the Apc -haploinsufficient mice ( Apc del/+ ) model MDS induced by an aberrant BM microenvironment...
June 1, 2017: Blood
Michael R Burgess, Eugene Hwang, Rana Mroue, Craig M Bielski, Anica M Wandler, Benjamin J Huang, Ari J Firestone, Amy Young, Jennifer A Lacap, Lisa Crocker, Saurabh Asthana, Elizabeth M Davis, Jin Xu, Keiko Akagi, Michelle M Le Beau, Qing Li, Benjamin Haley, David Stokoe, Deepak Sampath, Barry S Taylor, Marie Evangelista, Kevin Shannon
Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition...
February 23, 2017: Cell
Kai Lee Yap, Larissa V Furtado, Kazuma Kiyotani, Emily Curran, Wendy Stock, Jennifer L McNeer, Sabah Kadri, Jeremy P Segal, Yusuke Nakamura, Michelle M Le Beau, Sandeep Gurbuxani, Gordana Raca
Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a molecular subtype of high-risk B-cell ALL characterized by formation of abnormal gene fusions involving tyrosine kinase (TK) and cytokine receptor genes and activation of TK signaling. Because of the diversity of associated genetic changes, the detection of Ph-like ALL cases currently requires multiple cytogenetic and molecular assays; thus, our goal was to develop a consolidated workflow for detecting genetic abnormalities in Ph-like ALL. We found that total and targeted RNA sequencing (RNAseq)-based approach allowed the detection of abnormal fusion transcripts (EBF1-PDGFRB, P2RY8-CRLF2, RCSD1-ABL1, and RCSD1-ABL2)...
April 2017: Leukemia & Lymphoma
Peter L Greenberg, Heinz Tuechler, Julie Schanz, Guillermo Sanz, Guillermo Garcia-Manero, Francesc Solé, John M Bennett, David Bowen, Pierre Fenaux, Francois Dreyfus, Hagop Kantarjian, Andrea Kuendgen, Alessandro Levis, Luca Malcovati, Mario Cazzola, Jaroslav Cermak, Christa Fonatsch, Michelle M Le Beau, Marilyn L Slovak, Otto Krieger, Michael Luebbert, Jaroslaw Maciejewski, Silvia M M Magalhaes, Yasushi Miyazaki, Michael Pfeilstöcker, Mikkael Sekeres, Wolfgang R Sperr, Reinhard Stauder, Sudhir Tauro, Peter Valent, Teresa Vallespi, Arjan A van de Loosdrecht, Ulrich Germing, Detlef Haase
No abstract text is available yet for this article.
October 20, 2016: Blood
Joseph Frederick, Yvan Saint Jean, Jean Frantz Lemoine, Ellen M Dotson, Kimberly E Mace, Michelle Chang, Laurence Slutsker, Arnaud Le Menach, John C Beier, Thomas P Eisele, Bernard A Okech, Valery Madsen Beau de Rochars, Keith H Carter, Joseph Keating, Daniel E Impoinvil
BACKGROUND: Haiti has a set a target of eliminating malaria by 2020. However, information on malaria vector research in Haiti is not well known. This paper presents results from a systematic review of the literature on malaria vector research, bionomics and control in Haiti. METHODS: A systematic search of literature published in French, Spanish and English languages was conducted in 2015 using Pubmed (MEDLINE), Google Scholar, EMBASE, JSTOR WHOLIS and Web of Science databases as well other grey literature sources such as USAID, and PAHO...
July 22, 2016: Malaria Journal
Michael Pfeilstöcker, Heinz Tuechler, Guillermo Sanz, Julie Schanz, Guillermo Garcia-Manero, Francesc Solé, John M Bennett, David Bowen, Pierre Fenaux, Francois Dreyfus, Hagop Kantarjian, Andrea Kuendgen, Luca Malcovati, Mario Cazzola, Jaroslav Cermak, Christa Fonatsch, Michelle M Le Beau, Marilyn L Slovak, Alessandro Levis, Michael Luebbert, Jaroslaw Maciejewski, Sigrid Machherndl-Spandl, Silvia M M Magalhaes, Yasushi Miyazaki, Mikkael A Sekeres, Wolfgang R Sperr, Reinhard Stauder, Sudhir Tauro, Peter Valent, Teresa Vallespi, Arjan A van de Loosdrecht, Ulrich Germing, Detlef Haase, Peter L Greenberg
In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database...
August 18, 2016: Blood
Xi Jiang, Jason Bugno, Chao Hu, Yang Yang, Tobias Herold, Jun Qi, Ping Chen, Sandeep Gurbuxani, Stephen Arnovitz, Jennifer Strong, Kyle Ferchen, Bryan Ulrich, Hengyou Weng, Yungui Wang, Hao Huang, Shenglai Li, Mary Beth Neilly, Richard A Larson, Michelle M Le Beau, Stefan K Bohlander, Jie Jin, Zejuan Li, James E Bradner, Seungpyo Hong, Jianjun Chen
Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancy. Overexpression and/or mutations of FLT3 have been shown to occur in the majority of cases of AML. Our analysis of a large-scale AML patient cohort (N = 562) indicates that FLT3 is particularly highly expressed in some subtypes of AML, such as AML with t(11q23)/MLL-rearrangements or FLT3-ITD. Such AML subtypes are known to be associated with unfavorable prognosis. To treat FLT3-overexpressing AML, we developed a novel targeted nanoparticle system: FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) nanosized dendriplex encapsulating miR-150, a pivotal tumor suppressor and negative regulator of FLT3 We show that the FLT3L-guided miR-150 nanoparticles selectively and efficiently target FLT3-overexpressing AML cells and significantly inhibit viability/growth and promote apoptosis of the AML cells...
August 1, 2016: Cancer Research
Xi Jiang, Chao Hu, Stephen Arnovitz, Jason Bugno, Miao Yu, Zhixiang Zuo, Ping Chen, Hao Huang, Bryan Ulrich, Sandeep Gurbuxani, Hengyou Weng, Jennifer Strong, Yungui Wang, Yuanyuan Li, Justin Salat, Shenglai Li, Abdel G Elkahloun, Yang Yang, Mary Beth Neilly, Richard A Larson, Michelle M Le Beau, Tobias Herold, Stefan K Bohlander, Paul P Liu, Jiwang Zhang, Zejuan Li, Chuan He, Jie Jin, Seungpyo Hong, Jianjun Chen
MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways...
April 26, 2016: Nature Communications
Daniel A Arber, Attilio Orazi, Robert Hasserjian, Jürgen Thiele, Michael J Borowitz, Michelle M Le Beau, Clara D Bloomfield, Mario Cazzola, James W Vardiman
The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added...
May 19, 2016: Blood
Sara E Meyer, Tingting Qin, David E Muench, Kohei Masuda, Meenakshi Venkatasubramanian, Emily Orr, Lauren Suarez, Steven D Gore, Ruud Delwel, Elisabeth Paietta, Martin S Tallman, Hugo Fernandez, Ari Melnick, Michelle M Le Beau, Scott Kogan, Nathan Salomonis, Maria E Figueroa, H Leighton Grimes
UNLABELLED: Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency...
May 2016: Cancer Discovery
Angela Stoddart, Zhijian Qian, Anthony A Fernald, Rachel J Bergerson, Jianghong Wang, Theodore Karrison, John Anastasi, Elizabeth T Bartom, Aaron L Sarver, Megan E McNerney, David A Largaespada, Michelle M Le Beau
No abstract text is available yet for this article.
June 2016: Haematologica
Aparna Vasanthakumar, Stephen Arnovitz, Rafael Marquez, Janet Lepore, George Rafidi, Anase Asom, Madison Weatherly, Elizabeth M Davis, Barbara Neistadt, Robert Duszynski, James W Vardiman, Michelle M Le Beau, Lucy A Godley, Jane E Churpek
BRCA1 is critical for maintenance of genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell function and are part of the Fanconi anemia (FA) double-strand break DNA repair pathway. The effects of complete BRCA1 deficiency on bone marrow (BM) function are unknown. To test the hypothesis that Brca1 is essential in hematopoiesis, we developed a conditional mouse model with Mx1-Cre-mediated Brca1 deletion. Mice lacking Brca1 in the BM have baseline cytopenias and develop spontaneous bone marrow failure or diverse hematologic malignancies by 6 months of age...
January 21, 2016: Blood
Jane E Churpek, Rafael Marquez, Barbara Neistadt, Kimberly Claussen, Ming K Lee, Matthew M Churpek, Dezheng Huo, Howard Weiner, Mekhala Bannerjee, Lucy A Godley, Michelle M Le Beau, Colin C Pritchard, Tom Walsh, Mary-Claire King, Olufunmilayo I Olopade, Richard A Larson
BACKGROUND: Risk factors for the development of therapy-related leukemia (TRL), an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Survivors of breast cancer (BC) now account for the majority of TRL cases, making the study of TRL risk factors in this population a priority. METHODS: Subjects with TRL after cytotoxic therapy for a primary BC were identified from the TRL registry at The University of Chicago...
January 15, 2016: Cancer
Sriram Sundaravel, Ryan Duggan, Tushar Bhagat, David L Ebenezer, Hui Liu, Yiting Yu, Matthias Bartenstein, Madhu Unnikrishnan, Subhradip Karmakar, Ting-Chun Liu, Ingrid Torregroza, Thomas Quenon, John Anastasi, Kathy L McGraw, Andrea Pellagatti, Jacqueline Boultwood, Vijay Yajnik, Andrew Artz, Michelle M Le Beau, Ulrich Steidl, Alan F List, Todd Evans, Amit Verma, Amittha Wickrema
Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients...
November 17, 2015: Proceedings of the National Academy of Sciences of the United States of America
Zejuan Li, Ping Chen, Rui Su, Yuanyuan Li, Chao Hu, Yungui Wang, Stephen Arnovitz, Miao He, Sandeep Gurbuxani, Zhixiang Zuo, Abdel G Elkahloun, Shenglai Li, Hengyou Weng, Hao Huang, Mary Beth Neilly, Shusheng Wang, Eric N Olson, Richard A Larson, Michelle M Le Beau, Jiwang Zhang, Xi Jiang, Minjie Wei, Jie Jin, Paul P Liu, Jianjun Chen
It is generally assumed that gain- and loss-of-function manipulations of a functionally important gene should lead to the opposite phenotypes. We show in this study that both overexpression and knockout of microRNA (miR)-126 surprisingly result in enhanced leukemogenesis in cooperation with the t(8;21) fusion genes AML1-ETO/RUNX1-RUNX1T1 and AML1-ETO9a (a potent oncogenic isoform of AML1-ETO). In accordance with our observation that increased expression of miR-126 is associated with unfavorable survival in patients with t(8;21) acute myeloid leukemia (AML), we show that miR-126 overexpression exhibits a stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem cells/leukemia initiating cells (LSCs/LICs) in mice than does miR-126 knockout...
October 22, 2015: Blood
Friederike Braulke, Catharina Müller-Thomas, Katharina Götze, Uwe Platzbecker, Ulrich Germing, Wolf-Karsten Hofmann, Aristoteles A N Giagounidis, Michael Lübbert, Peter L Greenberg, John M Bennett, Francesc Solé, Marilyn L Slovak, Kazuma Ohyashiki, Michelle M Le Beau, Heinz Tüchler, Michael Pfeilstöcker, Barbara Hildebrandt, Carlo Aul, Reinhard Stauder, Peter Valent, Christa Fonatsch, Ulrike Bacher, Lorenz Trümper, Detlef Haase, Julie Schanz
In myelodysplastic syndromes (MDS), deletion of the short arm of chromosome 12 (del(12p)) is usually a small abnormality, rarely detected as a single aberration by chromosome banding analysis (CBA) of bone marrow metaphases. Del(12p) has been described in 0.6 to 5% of MDS patients at initial diagnosis and is associated with a good to intermediate prognosis as a sole anomaly according to current scoring systems. Here, we present the results of a systematic del(12p) testing in a German prospective diagnostic study (clinicaltrials...
December 2015: Genes, Chromosomes & Cancer
Giovanni Amabile, Annalisa Di Ruscio, Fabian Müller, Robert S Welner, Henry Yang, Alexander K Ebralidze, Hong Zhang, Elena Levantini, Lihua Qi, Giovanni Martinelli, Thijn Brummelkamp, Michelle M Le Beau, Maria E Figueroa, Christoph Bock, Daniel G Tenen
Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22)(q34;q11.2) encoding for the BCR-ABL fusion oncogene. However, many molecular mechanisms of the disease progression still remain poorly understood. A growing body of evidence suggests that the epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukaemic clone escape and disease propagation. Here we show that, by applying cellular reprogramming to primary CML cells, aberrant DNA methylation contributes to the disease evolution...
2015: Nature Communications
Zhen Zhao, Chi-Chao Chen, Cory D Rillahan, Ronglai Shen, Thomas Kitzing, Megan E McNerney, Ernesto Diaz-Flores, Johannes Zuber, Kevin Shannon, Michelle M Le Beau, Mona S Spector, Scott C Kogan, Scott W Lowe
RAS network activation is common in human cancers, and in acute myeloid leukemia (AML) this activation is achieved mainly through gain-of-function mutations in KRAS, NRAS or the receptor tyrosine kinase FLT3. We show that in mice, premalignant myeloid cells harboring a Kras(G12D) allele retained low levels of Ras signaling owing to negative feedback involving Spry4 that prevented transformation. In humans, SPRY4 is located on chromosome 5q, a region affected by large heterozygous deletions that are associated with aggressive disease in which gain-of-function mutations in the RAS pathway are rare...
May 2015: Nature Genetics
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