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https://www.readbyqxmd.com/read/29083320/pharmacological-inhibition-of-the-transcription-factor-pu-1-in-leukemia
#1
Iléana Antony-Debré, Ananya Paul, Joana Leite, Kelly Mitchell, Hye Mi Kim, Luis A Carvajal, Tihomira I Todorova, Kenneth Huang, Arvind Kumar, Abdelbasset A Farahat, Boris Bartholdy, Swathi-Rao Narayanagari, Jiahao Chen, Alberto Ambesi-Impiombato, Adolfo A Ferrando, Ioannis Mantzaris, Evripidis Gavathiotis, Amit Verma, Britta Will, David W Boykin, W David Wilson, Gregory Mk Poon, Ulrich Steidl
The transcription factor PU.1 is often impaired in patients with acute myeloid leukemia (AML). Here, we used AML cells that already had low PU.1 levels and further inhibited PU.1 using either RNA interference or, to our knowledge, first-in-class small-molecule inhibitors of PU.1 that we developed specifically to allosterically interfere with PU.1-chromatin binding through interaction with the DNA minor groove that flanks PU.1-binding motifs. These small molecules of the heterocyclic diamidine family disrupted the interaction of PU...
October 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29017059/direct-activation-of-bax-by-btsa1-overcomes-apoptosis-resistance-in-acute-myeloid-leukemia
#2
Denis E Reyna, Thomas P Garner, Andrea Lopez, Felix Kopp, Gaurav S Choudhary, Ashwin Sridharan, Swathi-Rao Narayanagari, Kelly Mitchell, Baoxia Dong, Boris A Bartholdy, Loren D Walensky, Amit Verma, Ulrich Steidl, Evripidis Gavathiotis
The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28986391/altered-hydroxymethylation-is-seen-at-regulatory-regions-in-pancreatic-cancer-and-regulates-oncogenic-pathways
#3
Sanchari Bhattacharyya, Kith Pradhan, Nathaniel Campbell, Jozef Mazdo, Aparna Vasantkumar, Shahina Maqbool, Tushar D Bhagat, Sonal Gupta, Masako Suzuki, Yiting Yu, John M Greally, Ulrich Steidl, James Bradner, Meelad Dawlaty, Lucy Godley, Anirban Maitra, Amit Verma
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers...
November 2017: Genome Research
https://www.readbyqxmd.com/read/28900037/znf143-is-an-important-regulator-of-the-myeloid-transcription-factor-c-ebp%C3%AE
#4
David Gonzalez, Annouck Luyten, Boris Bartholdy, Qiling Zhou, Miroslava Kardosova, Alex Ebralidze, Kenneth D Swanson, Hanna Radomska, Pu Zhang, Susumu S Kobayashi, Robert S Welner, Elena Levantini, Ulrich Steidl, Gilbert Chong, Samuel Collombet, Min Hee Choi, Alan D Friedman, Linda M Scott, Meritxell Alberich-Jorda, Daniel G Tenen
The transcription factor (TF) C/EBPα is essential for myeloid differentiation and is frequently dysregulated in acute myeloid leukemia (AML). While studied extensively, the precise regulation of its gene by upstream factors has remained largely elusive. Here, we investigated its transcriptional activation during myeloid differentiation. We identified an evolutionarily conserved octameric sequence, CCCAGCAG, approximately 100 bases upstream of the CEBPA transcription start site (TSS), and demonstrated through mutational analysis that this sequence is crucial for C/EBPα expression...
September 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28684528/epigenetically-aberrant-stroma-in-mds-propagates-disease-via-wnt-%C3%AE-catenin-activation
#5
Tushar D Bhagat, Si Chen, Matthias Bartenstein, A Trevor Barlowe, Dagny Von Ahrens, Gaurav S Choudhary, Patrick Tivnan, Elianna Amin, A Mario Marcondes, Mathijs A Sanders, Remco M Hoogenboezem, Suman Kambhampati, Nandini Ramachandra, Iaonnis Mantzaris, Vineeth Sukrithan, Remi Laurence, Robert Lopez, Prafullla Bhagat, Orsi Giricz, Davendra Sohal, Amittha Wickrema, Cecilia Yeung, Kira Gritsman, Peter Aplan, Konrad Hochedlinger, Yiting Yu, Kith Pradhan, Jinghang Zhang, John M Greally, Siddhartha Mukherjee, Andrea Pellagatti, Jacqueline Boultwood, Britta Will, Ulrich Steidl, Marc H G P Raaijmakers, H Joachim Deeg, Michael G Kharas, Amit Verma
The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28405618/efficacy-of-alk5-inhibition-in-myelofibrosis
#6
Lanzhu Yue, Matthias Bartenstein, Wanke Zhao, Wanting Tina Ho, Ying Han, Cem Murdun, Adam W Mailloux, Ling Zhang, Xuefeng Wang, Anjali Budhathoki, Kith Pradhan, Franck Rapaport, Huaquan Wang, Zonghong Shao, Xiubao Ren, Ulrich Steidl, Ross L Levine, Zhizhuang Joe Zhao, Amit Verma, Pearlie K Epling-Burnette
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28292433/eto2-glis2-a-chimeric-transcription-factor-drives-leukemogenesis-through-a-neomorphic-transcription-network
#7
COMMENT
Justin C Wheat, Ulrich Steidl
Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease with a relatively poorly understood pathogenesis. In this issue of Cancer Cell, Thirant and colleagues systematically examine unique transcriptional and functional effects of ETO2-GLIS2, an oncogenic fusion protein frequently encountered in AMKL, and elucidate a therapeutic vulnerability in this poor-prognosis leukemia.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28159737/stem-and-progenitor-cell-alterations-in-myelodysplastic-syndromes
#8
REVIEW
Aditi Shastri, Britta Will, Ulrich Steidl, Amit Verma
Recent studies have demonstrated that myelodysplastic syndromes (MDSs) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse. MDS stem and progenitor cells are characterized by key founder and driver mutations and are enriched for cytogenetic alterations. Quantitative alterations in hematopoietic stem and progenitor cell (HSPC) numbers are also seen in a stage-specific manner in human MDS samples as well as in murine models of the disease...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/27597933/dnmt3a-and-tet2-in-the-pre-leukemic-phase-of-hematopoietic-disorders
#9
REVIEW
Hanae Sato, Justin C Wheat, Ulrich Steidl, Keisuke Ito
In recent years, advances in next-generation sequencing (NGS) technology have provided the opportunity to detect putative genetic drivers of disease, particularly cancers, with very high sensitivity. This knowledge has substantially improved our understanding of tumor pathogenesis. In hematological malignancies such as acute myeloid leukemia and myelodysplastic syndromes, pioneering work combining multi-parameter flow cytometry and targeted resequencing in leukemia have clearly shown that different classes of mutations appear to be acquired in particular sequences along the hematopoietic differentiation hierarchy...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27392220/eliminating-cancer-stem-cells-in-cml-with-combination-transcriptional-therapy
#10
COMMENT
Luis A Carvajal, Ulrich Steidl
Leukemia stem cells (LSCs) are resistant to current therapies used to treat chronic myeloid leukemia (CML). Abraham et al. (2016) have identified a molecular network critical for CML LSC survival and propose that simultaneously targeting two of their major transcriptional regulators, p53 and c-Myc, may facilitate their eradication.
July 7, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27175029/targeted-positron-emission-tomography-imaging-of-cxcr4-expression-in-patients-with-acute-myeloid-leukemia
#11
Peter Herhaus, Stefan Habringer, Kathrin Philipp-Abbrederis, Tibor Vag, Carlos Gerngross, Margret Schottelius, Julia Slotta-Huspenina, Katja Steiger, Torben Altmann, Tanja Weißer, Sabine Steidle, Markus Schick, Laura Jacobs, Jolanta Slawska, Catharina Müller-Thomas, Mareike Verbeek, Marion Subklewe, Christian Peschel, Hans-Jürgen Wester, Markus Schwaiger, Katharina Götze, Ulrich Keller
Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression...
August 2016: Haematologica
https://www.readbyqxmd.com/read/27144332/analysis-of-overall-survival-in-a-large-multiethnic-cohort-reveals-absolute-neutrophil-count-of-1-100-as-a-novel-prognostic-cutoff-in-african-americans
#12
Ioannis Mantzaris, Yiting Yu, Pavlos Msaouel, Anthony P Lam, Murali Janakiram, Ellen W Friedman, Ulrich Steidl, Amit K Verma
Although absolute neutrophil counts (ANC) below 1.5x103/uL are used to define neutropenia as a marker of increased susceptibility to infections, their relationship with survival has not been examined. Since low counts trigger extensive investigations, determining prognostic cutoffs especially for different ethnicities and races is critical.A multiethnic cohort of 27,760 subjects, 65 years old and above, was utilized to evaluate the association of neutropenia with overall survival in different ethnicities and races...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27111842/chronic-interleukin-1-exposure-drives-haematopoietic-stem-cells-towards-precocious-myeloid-differentiation-at-the-expense-of-self-renewal
#13
Eric M Pietras, Cristina Mirantes-Barbeito, Sarah Fong, Dirk Loeffler, Larisa V Kovtonyuk, SiYi Zhang, Ranjani Lakshminarasimhan, Chih Peng Chin, José-Marc Techner, Britta Will, Claus Nerlov, Ulrich Steidl, Markus G Manz, Timm Schroeder, Emmanuelle Passegué
Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory 'emergency' signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program...
June 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27045016/molecular-mechanism-of-mutant-calr-mediated-transformation
#14
COMMENT
Robert F Stanley, Ulrich Steidl
Elf and colleagues used an elegant series of functional and biochemical assays to investigate the molecular mechanism of mutant calreticulin (CALR)-driven cellular transformation in myeloproliferative neoplasms (MPN). Mutant CALR is sufficient to induce MPN in mouse transplantation experiments, and transformation is dependent upon physical interaction mediated by the positive electrostatic charge of the mutant CALR C-terminal domain and the thrombopoietin receptor MPL.
April 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27013212/ectopic-dnmt3b-expression-delays-leukemogenesis
#15
COMMENT
Robert F Stanley, Ulrich Steidl
In this issue of Blood, Schulze et al use a tetracycline-inducible Dnmt3b knock-in mouse model to investigate how DNMT3B-mediated DNA methylation affects leukemogenesis. Increased DNMT3B expression prolonged survival in retrovirally induced Myc-Bcl2– or MLL-AF9–driven leukemia, and acute myeloid leukemia (AML) patients with high expression of DNMT3B target genes showed inferior overall survival.
March 24, 2016: Blood
https://www.readbyqxmd.com/read/26578796/reduced-dock4-expression-leads-to-erythroid-dysplasia-in-myelodysplastic-syndromes
#16
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
https://www.readbyqxmd.com/read/26436839/new-idh1-mutant-inhibitors-for-treatment-of-acute-myeloid-leukemia
#17
Ujunwa C Okoye-Okafor, Boris Bartholdy, Jessy Cartier, Enoch N Gao, Beth Pietrak, Alan R Rendina, Cynthia Rominger, Chad Quinn, Angela Smallwood, Kenneth J Wiggall, Alexander J Reif, Stanley J Schmidt, Hongwei Qi, Huizhen Zhao, Gerard Joberty, Maria Faelth-Savitski, Marcus Bantscheff, Gerard Drewes, Chaya Duraiswami, Pat Brady, Arthur Groy, Swathi-Rao Narayanagari, Iléana Antony-Debre, Kelly Mitchell, Heng Rui Wang, Yun-Ruei Kao, Maximilian Christopeit, Luis Carvajal, Laura Barreyro, Elisabeth Paietta, Hideki Makishima, Britta Will, Nestor Concha, Nicholas D Adams, Benjamin Schwartz, Michael T McCabe, Jaroslav Maciejewski, Amit Verma, Ulrich Steidl
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo...
November 2015: Nature Chemical Biology
https://www.readbyqxmd.com/read/26343801/minimal-pu-1-reduction-induces-a-preleukemic-state-and-promotes-development-of-acute-myeloid-leukemia
#18
Britta Will, Thomas O Vogler, Swathi Narayanagari, Boris Bartholdy, Tihomira I Todorova, Mariana da Silva Ferreira, Jiahao Chen, Yiting Yu, Jillian Mayer, Laura Barreyro, Luis Carvajal, Daniela Ben Neriah, Michael Roth, Johanna van Oers, Sonja Schaetzlein, Christine McMahon, Winfried Edelmann, Amit Verma, Ulrich Steidl
Modest transcriptional changes caused by genetic or epigenetic mechanisms are frequent in human cancer. Although loss or near-complete loss of the hematopoietic transcription factor PU.1 induces acute myeloid leukemia (AML) in mice, a similar degree of PU.1 impairment is exceedingly rare in human AML; yet, moderate PU.1 inhibition is common in AML patients. We assessed functional consequences of modest reductions in PU.1 expression on leukemia development in mice harboring DNA lesions resembling those acquired during human stem cell aging...
October 2015: Nature Medicine
https://www.readbyqxmd.com/read/26170031/pak1-is-a-therapeutic-target-in-acute-myeloid-leukemia-and-myelodysplastic-syndrome
#19
Ashley Pandolfi, Robert F Stanley, Yiting Yu, Boris Bartholdy, Gopichand Pendurti, Kira Gritsman, Jacqueline Boultwood, Jonathan Chernoff, Amit Verma, Ulrich Steidl
Poor clinical outcome of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia inhibitory effects both in vitro and in vivo...
August 27, 2015: Blood
https://www.readbyqxmd.com/read/25965566/functionally-relevant-rna-helicase-mutations-in-familial-and-sporadic-myeloid-malignancies
#20
COMMENT
Iléana Antony-Debré, Ulrich Steidl
In this issue of Cancer Cell, Polprasert and colleagues identified recurrent mutations in the DEAD/H-box RNA helicase gene DDX41 in familial and acquired cases of myelodsyplasia and acute myeloid leukemia. These mutations induce defects in RNA splicing and represent a new class of mutations in myeloid malignancies.
May 11, 2015: Cancer Cell
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