journal

Blood

journal
https://read.qxmd.com/read/32232485/aml-displays-increased-ctcf-occupancy-associated-to-aberrant-gene-expression-and-transcription-factor-binding
#1
Huthayfa Mujahed, Sophia Miliara, Anne Helene Neddermeyer, Sofia Bengtzen, Christer Nilsson, Stefan Deneberg, Lina Cordeddu, Karl Ekwall, Andreas Lennartsson, Sören Lehmann
CTCF is a key regulator of gene expression through organization of the chromatin structure. Still, it is unclear how CTCF binding is perturbed in leukemia or in cancer in general. We studied CTCF binding by ChIP-Seq in cells from patients with acute myeloid leukemia (AML) and in normal bone marrow (NBM) in the context of gene expression, DNA methylation and azacytidine exposure. CTCF binding was increased in AML compared to NBM. Aberrant CTCF binding was enriched for motifs for key myeloid transcription factors such as CEBPA, PU...
March 31, 2020: Blood
https://read.qxmd.com/read/32232483/an-intestinal-organoid-based-platform-that-recreates-susceptibility-to-t-cell-mediated-tissue-injury
#2
Yu Matsuzawa-Ishimoto, Ashley Hine, Yusuke Shono, Eugene Rudensky, Amina Lazrak, Frank Yeung, Jessica A Neil, Xiaomin Yao, Ying-Han Chen, Thomas Heaney, Samantha L Schuster, Erin E Zwack, Jordan Eric Axelrad, David Hudesman, Jennifer Jia-Ying Tsai, Katherine B Nichols, M Zahidunnabi Dewan, Michael Cammer, Allison Beal, Sandra Hoffman, Brad Geddes, John Bertin, Chen Liu, Victor J Torres, P'ng Loke, Marcel Rm van den Brink, Ken Cadwell
A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis...
March 30, 2020: Blood
https://read.qxmd.com/read/32219447/atypical-3q26-mecom-rearrangements-genocopy-inv-3-t-3-3-in-acute-myeloid-leukemia
#3
Sophie Ottema, Roger Mulet-Lazaro, H Berna Beverloo, Claudia A J Erpelinck, Stanley van Herk, Robert van der Helm, Marije Havermans, Tim Grob, Peter Valk, Eric Bindels, Torsten Haferlach, Claudia Haferlach, Leonie Smeenk, Ruud Delwel
Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct WHO recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML...
March 27, 2020: Blood
https://read.qxmd.com/read/32219446/genetic-disruption-of-n-rasg12d-palmitoylation-perturbs-hematopoiesis-and-prevents-myeloid-transformation-in-mice
#4
Naomi A Zambetti, Ari J Firestone, Jarrett R Remsberg, Benjamin J Huang, Jasmine C Wong, Amanda M Long, Marina Predovic, Radu M Suciu, Anagha Inguva, Scott C Kogan, Kevin M Haigis, Benjamin F Cravatt, Kevin Shannon
Oncogenic RAS mutations pose substantial challenges for rational drug discovery. Sequence variations within the hypervariable region (HVR) of Ras isoforms underlie differential post-translational modification and subcellular trafficking, potentially resulting in selective vulnerabilities. Specifically, inhibiting the palmitoylation/depalmitoylation cycle is an appealing strategy for treating NRAS mutant cancers, particularly as normal tissues would retain K-Ras4b function for physiologic signaling. The role of endogenous N-RasG12D palmitoylation in signal transduction, hematopoietic differentiation, and myeloid transformation are unknown and addressing these key questions will inform efforts to develop mechanism-based therapies...
March 27, 2020: Blood
https://read.qxmd.com/read/32219445/calreticulin-haploinsufficiency-augments-stem-cell-activity-and-is-required-for-onset-of-myeloproliferative-neoplasms
#5
Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Yoshinori Ozono, Yuki Tahira, Takako Yokomizo-Nakano, Sho Kubota, Masaya Ono, Kazuhiko Ikeda, Masaaki Sekine, Keiichi Akizuki, Kenichi Nakamura, Tomonori Hidaka, Yoko Kubuki, Hisayoshi Iwakiri, Satoru Hasuike, Kenji Nagata, Goro Sashida, Kazuya Shimoda
Mutations in JAK2, MPL, or CALR are detected in more than 80% of myeloproliferative neoplasm (MPN) patients and are thought to play a driver role in MPN pathogenesis via autosomal activation of the JAK-STAT signaling cascade. Mutant CALR binds to MPL, activates downstream MPL signaling cascades, and induces essential thrombocythemia in mice. However, embryonic lethality of Calr-deficient mice precludes determination of a role for CALR in hematopoiesis. To clarify the role of CALR in normal hematopoiesis and MPN pathogenesis, we generated hematopoietic cell-specific Calr-deficient mice...
March 27, 2020: Blood
https://read.qxmd.com/read/32219444/integrin-%C3%AE-6-mediates-drug-resistance-of-acute-lymphoblastic-b-cell-leukemia
#6
Eun Ji Gang, Hye Na Kim, Yao Te Hsieh, Yongsheng Ruan, Heather Ogana, Jennifer Pham, Solomon Lee, Huimin Geng, Eugene Park, Lars Klemm, Cheryl L Willman, William L Carroll, Steven D Mittelman, Etan Orgel, Matthew James Oberley, Chintan Parekh, Hisham Abdel-Azim, Deepa Bhojwani, Alan S Wayne, Adele De Arcangelis, Elisabeth Georges-Labouesse, Elizabeth Wayner, Halvard B Bönig, Aspram Minasyan, Johanna Ten Hoeve, Thomas Graeber, Markus Müschen, Nora Heisterkamp, Yong-Mi Kim
Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking antibody P5G10 induces apoptosis in primary ALL in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo...
March 27, 2020: Blood
https://read.qxmd.com/read/32219443/aromatase-is-a-novel-neo-substrate-of-cereblon-responsible-for-immunomodulatory-drugs-induced-thrombocytopenia
#7
Taro Tochigi, Toshihiro Miyamoto, Kiwamu Hatakeyama, Teppei Sakoda, Daisuke Ishihara, Hidetoshi Irifune, Takahiro Shima, Koji Kato, Takahiro Maeda, Takumi Ito, Hiroshi Handa, Koichi Akashi, Yoshikane Kikushige
Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neo-substrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell specific neo-substrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia that frequently results in the discontinuation of IMiDs treatment...
March 27, 2020: Blood
https://read.qxmd.com/read/32219442/venetoclax-plus-ldac-for-patients-with-untreated-aml-ineligible-for-intensive-chemotherapy-phase-3-randomized-placebo-controlled-trial
#8
Andrew Henry Wei, Pau Montesinos, Vladimir Ivanov, Courtney D DiNardo, Jan Novak, Kamel Laribi, Inho Kim, Don Stevens, Walter Fiedler, Maria Pagoni, Olga Samoilova, Yu Hu, Achilles Anagnostopoulos, Julie Bergeron, Jing-Zhou Hou, Vidhya Murthy, Takahiro Yamauchi, Andrew Bruce McDonald, Brenda Chyla, Sathej Gopalakrishnan, Qi Jiang, Wellington L Mendes, John Hayslip, Panayiotis Panayiotidis
BACKGROUND: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. METHODS: Adults ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international Phase 3 randomized, double-blind, placebo-controlled trial. Patients (N=211) were randomized 2:1 to either: venetoclax (N=143) or placebo (N=68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1-10...
March 27, 2020: Blood
https://read.qxmd.com/read/32211877/stage-i-ii-nodular-lymphocyte-predominant-hodgkin-lymphoma-a-multi-institutional-experience-of-adult-patients-by-ilrog
#9
Michael S Binkley, M Shahzad Rauf, Sarah A Milgrom, Chelsea C Pinnix, Richard W Tsang, Michael Dickinson, Andrea Ng, Kenneth B Roberts, Sarah Gao, Alexander George Balogh, Umberto Ricardi, Mario Levis, Carla Casulo, Michael Stolten, Lena Specht, John Peter Plastaras, Christopher Wright, Chris R Kelsey, Jessica L Brady, N George Mikhaeel, Bradford S Hoppe, Stephanie Terezakis, Marco Picardi, Roberta Della Pepa, Youlia Kirova, Saad Akhtar, Irfan Maghfoor, Julie L Koenig, Christopher Jackson, Erin Song, Shuchi Sehgal, Ranjana Advani, Yasodha Natkunam, Louis S Constine, Hans T Eich, Andrew Wirth, Richard T Hoppe
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment for stage I-II NLPHL is undefined. We conducted a multi-center retrospective study including patients ≥16 years with stage I-II NLPHL diagnosed from 1995-2018 receiving all forms of management including radiotherapy (RT), combined modality therapy (CMT=RT+chemotherapy), chemotherapy (CT), observation after excision, rituximab and RT, and single agent rituximab (R). End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups...
March 25, 2020: Blood
https://read.qxmd.com/read/32232486/novel-bcl2-mutations-in-venetoclax-resistant-ibrutinib-resistant-cll-patients-with-btk-plcg2-mutations
#10
Fabienne Lucas, Karilyn Larkin, Charles Thomas Gregory, Shelley Orwick, Tzyy-Jye Doong, Arletta Lozanski, Gerard Lozanski, Shrilekha Misra, Apollinaire Ngankeu, Hatice Gulcin Ozer, Deepa Sampath, Shanmugapriya Thangavadivel, Ayse Selen Yilmaz, Kerry A Rogers, John Byrd, Jennifer A Woyach, James S Blachly
No abstract text is available yet for this article.
March 24, 2020: Blood
https://read.qxmd.com/read/32206779/increased-mtor-activation-in-idiopathic-multicentric-castleman-disease
#11
Daniel J Arenas, Katherine Floess, Dale Kobrin, Ruth-Anne Langan Pai, Maya Blanka Srkalovic, Mark-Avery Tamakloe, Rozena Rasheed, Jasira Ziglar, Johnson Khor, Sophia A T Parente, Sheila K Pierson, Daniel Martinez, Gerald B Wertheim, Taku Kambayashi, Joseph Baur, David T Teachey, David C Fajgenbaum
Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for non-responders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported three anti-IL-6 non-responders with increased mTOR activation who responded to mTOR inhibition with sirolimus...
March 23, 2020: Blood
https://read.qxmd.com/read/32206775/establishment-of-a-human-sirpa-knock-in-xenograft-mouse-model-to-study-human-hematopoietic-and-cancer-stem-cells
#12
Fumiaki Jinnouchi, Takuji Yamauchi, Ayano Yurino, Takuya Nunomura, Michitaka Nakano, Chika Iwamoto, Teppei Obara, Kohta Miyawaki, Yoshikane Kikushige, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Eishi Baba, Koichi Akashi, Katsuto Takenaka
In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In the present study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman), in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages in C57BL/6 with Sirpahuman/human had an affinity for human CD47 significantly stronger than those with SirpaNOD/NOD, and did not show detectable phagocytosis against human hematopoietic stem cells...
March 23, 2020: Blood
https://read.qxmd.com/read/32206772/prognostic-and-predictive-impact-of-genetic-markers-in-patients-with-cll-treated-with-obinutuzumab-and-venetoclax
#13
Eugen Tausch, Christof Schneider, Sandra Robrecht, Can Zhang, Anna Dolnik, Johannes Bloehdorn, Jasmin Bahlo, Othman Al-Sawaf, Matthias Ritgen, Anna Maria Fink, Barbara Eichhorst, Karl-Anton Kreuzer, Maneesh Tandon, Kathryn Humphrey, Yanwen Jiang, William Schary, Lars Bullinger, Daniel Mertens, Michele Porro Lurà, Michael Kneba, Hartmut Döhner, Kirsten Fischer, Michael Hallek, Stephan Stilgenbauer
Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy but less well studied with novel compounds. We assessed IGHV mutation status, common genomic aberrations and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942) comparing obinutuzumab+chlorambucil (GClb) vs. obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +(12) 18% and del(13q) 35%, while IGHV was unmutated in 60% of patients...
March 23, 2020: Blood
https://read.qxmd.com/read/32202637/clinical-and-biological-implications-of-target-occupancy-in-cll-treated-with-the-btk-inhibitor-acalabrutinib
#14
Clare Chui Ling Sun, Pia K Nierman, Ellen K Kendall, Jean Cheung, Michael Gulrajani, Sarah E M Herman, Christopher Pleyer, Inhye E Ahn, Maryalice Stetler-Stevenson, Constance Yuan, Irina Maric, Erika M Gaglione, Hailey M Harris, Stefania Pittaluga, Min Hui Wang, Priti Patel, Mohammed Zh Farooqui, Raquel Izumi, Ahmed Hamdy, Todd Covey, Adrian Wiestner
Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined...
March 20, 2020: Blood
https://read.qxmd.com/read/32202636/setd2-deficiency-predicts-poor-prognosis-in-mds-and-accelerated-mds-associated-leukemogenesis-via-s100a9
#15
Bing-Yi Chen, Junhong Song, Cheng-Long Hu, Shu-Bei Chen, Qunling Zhang, Chun-Hui Xu, Ji-Chuan Wu, Dan Hou, Ming Sun, Yuan-Liang Zhang, Na Liu, Peng-Cheng Yu, Ping Liu, Li-Juan Zong, Jia-Ying Zhang, Ruo-Fei Dai, Fei Lan, Qiuhua Huang, Sujiang Zhang, Stephen D Nimer, Zhu Chen, Sai-Juan Chen, Xiao-Jian Sun, Lan Wang
SETD2, the histone H3 lysine 36 methyltransferase previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in MDS has been unclear. In this study, we show that low expression of SETD2 correlates with shortened survival in MDS patients and that the SETD2 levels in CD34+ bone marrow (BM) cells of MDS patients can be increased by decitabine. We knock out Setd2 in the NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and demonstrate that loss of Setd2 accelerates the transformation of MDS into acute myeloid leukemia (AML)...
March 20, 2020: Blood
https://read.qxmd.com/read/32202634/the-role-of-agk-in-thrombocytopoiesis-and-possible-therapeutic-strategies
#16
Haojie Jiang, Zhuo Yu, Nan Ding, Mina Yang, Lin Zhang, Xuemei Fan, Yuan Zhou, Qiang Zou, Jian Hou, Junke Zheng, Lei Zhang, Yanyan Xu, Junling Liu
Abnormal megakaryocyte development and platelet production lead to thrombocytopenia or thrombocythemia and increase the risk of hemorrhage or thrombosis. AGK is a mitochondrial membrane kinase that catalyzes the formation of phosphatidic acid and lysophosphatidic acid. Mutation of AGK has been described as the major cause of Sengers syndrome, and the patients with Sengers syndrome have been reported to exhibit thrombocytopenia. In this study, we found that megakaryocyte/platelet-specific AGK-deficient mice developed thrombocytopenia and splenomegaly, mainly caused by inefficient bone marrow thrombocytopoiesis and excessive extramedullary hematopoiesis but not by apoptosis of circulating platelets...
March 20, 2020: Blood
https://read.qxmd.com/read/32202632/introduction-to-how-i-treat-series-on-common-medical-problems-after-allogeneic-stem-cell-transplantation
#17
Robert Zeiser
No abstract text is available yet for this article.
March 20, 2020: Blood
https://read.qxmd.com/read/32202631/how-i-treat-cmv-reactivation-after-allogeneic-hematopoietic-stem-cell-transplantation
#18
Hermann Einsele, Per T Ljungman, Michael J Boeckh
CMV reactivation remains one of the most common and life-threatening infectious complications following allogeneic hematopoietic stem cell transplantation (allo-HCT) in spite of novel diagnostic technologies, several novel prophylactic agents and further improvement in preemptive therapy and treatment for established CMV disease. Today treatment decisions for CMV reactivation are becoming increasingly difficult and have to consider whether the patient has received antiviral prophylaxis, the patient`s individual risk profile for CMV disease, CMV-specific T cell reconstitution as well as both the CMV viral load and the potential drug-resistance detected at the time of initiation of antiviral therapy...
March 20, 2020: Blood
https://read.qxmd.com/read/32202630/how-i-treat-steroid-refractory-acute-graft-versus-host-disease
#19
Paul J Martin
Steroid-resistant or refractory acute GVHD (SR-aGVHD) poses one of the most vexing challenges faced by providers who care for patients after allogeneic hematopoietic cell transplantation. For the past 4 decades, research in the field been driven by the premise that persistent GVHD results from inadequate immunosuppression. Accordingly, most efforts to solve this problem have relied on retrospective or prospective studies testing agents that have direct or indirect immunosuppressive effects. Retrospective studies far outnumber prospective studies, and no controlled prospective trial has shown superior results for any agent over others...
March 20, 2020: Blood
https://read.qxmd.com/read/32187362/erdheim-chester-disease-consensus-recommendations-for-the-evaluation-diagnosis-and-treatment-in-the-molecular-era
#20
Gaurav Goyal, Mark L Heaney, Matthew Collin, Fleur Cohen Aubart, Augusto Vaglio, Benjamin H Durham, Oshrat Hershkovitz-Rokah, Michael Girschikofsky, Eric D Jacobsen, Kazuhiro Toyama, Aaron Michael Goodman, Paul Hendrie, Xin-Xin Cao, Juvianee Estrada-Veras, Ofer Shpilberg, Andre Abdo, Mineo Kurokawa, Lorenzo Dagna, Kenneth L McClain, Roei D Mazor, Jennifer Picarsic, Filip Janku, Ronald S Go, Julien Haroche, Eli Diamond
Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAP-kinase (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to non-specific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays...
March 18, 2020: Blood
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