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https://www.readbyqxmd.com/read/28530640/genetic-regulation-of-the-runx-transcription-factor-family-has-antitumor-effects
#1
Ken Morita, Kensho Suzuki, Shintaro Maeda, Akihiko Matsuo, Yoshihide Mitsuda, Chieko Tokushige, Gengo Kashiwazaki, Junichi Taniguchi, Rina Maeda, Mina Noura, Masahiro Hirata, Tatsuki Kataoka, Ayaka Yano, Yoshimi Yamada, Hiroki Kiyose, Mayu Tokumasu, Hidemasa Matsuo, Sunao Tanaka, Yasushi Okuno, Manabu Muto, Kazuhito Naka, Kosei Ito, Toshio Kitamura, Yasufumi Kaneda, Paul P Liu, Toshikazu Bando, Souichi Adachi, Hiroshi Sugiyama, Yasuhiko Kamikubo
Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members...
May 22, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28529810/molecular-profiling-a-case-of-zbtb16-rara-acute-promyelocytic-leukemia
#2
Stephen E Langabeer, Lisa Preston, Johanna Kelly, Matt Goodyer, Ezzat Elhassadi, Amjad Hayat
Several variant RARA translocations have been reported in acute promyelocytic leukemia (APL) of which the t(11;17)(q23;q21), which results in a ZBTB16-RARA fusion, is the most widely identified and is largely resistant to therapy with all-trans retinoic acid (ATRA). The clinical course together with the cytogenetic and molecular characterization of a case of ATRA-unresponsive ZBTB16-RARA APL is described. Additional mutations potentially cooperating with the translocation fusion product in leukemogenesis have been hitherto unreported in ZBTB16-RARA APL and were sought by application of a next-generation sequencing approach to detect those recurrently found in myeloid malignancies...
2017: Case Reports in Hematology
https://www.readbyqxmd.com/read/28529313/impact-of-killer-immunoglobulin-like-receptor-and-human-leukocyte-antigen-genotypes-on-the-efficacy-of-immunotherapy-in-acute-myeloid-leukemia
#3
E Bernson, A Hallner, F E Sander, O Wilsson, O Werlenius, A Rydström, R Kiffin, M Brune, R Foà, J Aurelius, A Martner, K Hellstrand, F B Thorén
Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), i.e. a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells...
May 22, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28529112/myeloid-differentiation-factor-88-is-up-regulated-in-epileptic-brain-and-contributes-to-experimental-seizures-in-rats
#4
Na Wang, Xiong Han, Haipeng Liu, Ting Zhao, Jie Li, Yan Feng, Xiujuan Mi, Yanke Zhang, Yanan Chen, Xuefeng Wang
Accumulating evidence supports that activation of inflammatory pathways is a crucial factor contributing to the pathogenesis of seizures. In particular, the activation of interleukin-1 beta (IL-1β) system exerts proconvulsant effects in a large variety of seizure models. Myeloid differentiation factor 88 (MyD88) is a critical adaptor protein in the signaling cascade elicited by IL-1β. The present study aimed to investigate the expression pattern of MyD88 in rat models of seizures and in patients with refractory temporal lobe epilepsy (TLE), and to study the role of MyD88 in epileptic seizures...
May 18, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28528711/clinical-impact-of-colonization-with-multidrug-resistant-organisms-on-outcome-after-autologous-stem-cell-transplantation-a-retrospective-single-center-study
#5
Sebastian Scheich, Claudia Reinheimer, Christian Brandt, Thomas A Wichelhaus, Michael Hogardt, Volkhard A J Kempf, Uta Brunnberg, Christian Brandts, Olivier Ballo, Ivana von Metzler, Johanna Kessel, Hubert Serve, Björn Steffen
During the last years, a significant increase in infections caused by multidrug-resistant organisms (MDRO) has been noticed, resulting in an increase of mortality in all fields of healthcare. Hematological patients are particularly affected by MDRO infections due to disease- and therapy-related immunosuppression. To determine the impact of colonization with MDRO on overall survival, we retrospectively analyzed data from patients undergoing autologous hematopoietic stem cell transplantation at our institution...
May 18, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28528702/detailed-characterization-of-mesenchymal-stem-stromal-cells-from-a-large-cohort-of-aml-patients-demonstrates-a-definitive-link-to-treatment-outcomes
#6
Rafael Diaz de la Guardia, Belen Lopez-Millan, Jessie R Lavoie, Clara Bueno, Julio Castaño, Maite Gómez-Casares, Susana Vives, Laura Palomo, Manel Juan, Julio Delgado, Maria L Blanco, Josep Nomdedeu, Alberto Chaparro, Jose Luis Fuster, Eduardo Anguita, Michael Rosu-Myles, Pablo Menéndez
Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup...
May 18, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28527984/personalized-prognostic-risk-score-for-long-term-survival-for-children-with-acute-leukemia-after-allogeneic-transplant
#7
Menachem Bitan, Kwang Woo Ahn, Heather R Millard, Michael A Pulsipher, Hisham Abdel-Azim, Jeffery J Auletta, Valerie Brown, Ka Wah Chan, Miguel Angel Diaz, Andrew Dietz, Marta González Vincent, Gregory Guilcher, Gregory A Hale, Robert J Hayashi, Amy Keating, Parinda Mehta, Kasiani Myers, Kristin Page, Tim Prestidge, Nirali N Shah, Angela R Smith, Ann Woolfrey, Elizabeth Thiel, Stella M Davies, Mary Eapen
We studied leukemia-free (LFS) and overall survival (OS) in children with acute myeloid (AML; n=790) and acute lymphoblastic leukemia (ALL; n=1096), transplanted between 2000 and 2010, who survived for at least 1 year in remission after related or unrelated donor transplantation. Analysis of patient-, disease- and transplantation characteristics and acute and chronic graft versus host disease (GVHD) were performed to identify factors with adverse effects on LFS and OS. These data were used to develop risk scores for survival...
May 17, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28527473/presence-of-new-mutations-in-the-tp53-gene-in-patients-with-low-risk-myelodysplastic-syndrome-two-case-reports
#8
Fernando Barroso Duarte, Romélia Pinheiro Gonçalves Lemes, Talyta Ellen de Jesus Dos Santos, Maritza Cavalcante Barbosa, João Paulo Leitão de Vasconcelos, Francisco Dário Rocha-Filho, Ilana Zalcberg, Diego Coutinho, Monalisa Feliciano Figueiredo, Luciana Barros Carlos, Paulo Roberto Leitão de Vasconcelos
BACKGROUND: Myelodysplastic syndromes are heterogeneous disorders. Patients with myelodysplastic syndrome disease often have ineffective hematopoiesis, cytopenias, blood cell dysplasia in one or more cell types, and are at high risk for developing acute myeloid leukemia. In myelodysplastic syndrome, mutations of TP53 gene are usually associated with complex karyotype and confer a worse prognosis. In the present study, two mutations in this gene are presented and discussed with the clinical evolution of the patients...
May 21, 2017: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/28526740/midostaurin-gets-fda-nod-for-aml
#9
(no author information available yet)
The FDA has approved the small-molecule inhibitor midostaurin in combination with chemotherapy to treat acute myeloid leukemia. It is the first approved drug for the disease that specifically targets FLT3 mutations, which occur in about a quarter of all AML cases and are associated with particularly poor outcomes.
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28526536/trastuzumab-emtansine-versus-capecitabine-plus-lapatinib-in-patients-with-previously-treated-her2-positive-advanced-breast-cancer-emilia-a-descriptive-analysis-of-final-overall-survival-results-from-a-randomised-open-label-phase-3-trial
#10
Véronique Diéras, David Miles, Sunil Verma, Mark Pegram, Manfred Welslau, José Baselga, Ian E Krop, Kim Blackwell, Silke Hoersch, Jin Xu, Marjorie Green, Luca Gianni
BACKGROUND: The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. METHODS: EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane...
May 16, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28525762/minimal-residual-disease-monitoring-of-acute-myeloid-leukemia-by-massively-multiplex-digital-pcr-in-patients-with-npm1-mutations
#11
Nuria Mencia-Trinchant, Yang Hu, Maria Antonina Alas, Fatima Ali, Bas J Wouters, Sangmin Lee, Ellen K Ritchie, Pinkal Desai, Monica L Guzman, Gail J Roboz, Duane C Hassane
The presence of minimal residual disease (MRD) is widely recognized as a powerful predictor of therapeutic outcome in acute myeloid leukemia (AML), but methods of measurement and quantification of MRD in AML are not yet standardized in clinical practice. There is an urgent, unmet need for robust and sensitive assays that can be readily adopted as real-time tools for disease monitoring. NPM1 frameshift mutations are an established MRD marker present in half of patients with cytogenetically normal AML. However, detection is complicated by the existence of hundreds of potential frameshift insertions, clonal heterogeneity, and absence of sequence information when the NPM1 mutation is identified using capillary electrophoresis...
May 16, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28525619/epidemiology-and-clinical-characteristics-of-invasive-mould-infections-a-multicenter-retrospective-analysis-in-five-asian-countries
#12
R Porpon, Y C Chen, A Chakrabarti, R Y Li, R M Shivaprakash, J Yu, H C Kung, S Watcharananan, A L Tan, S E Saffari, B H Tan
Formal, large-scale, multicenter studies of invasive mould infection (IMI) in Asia are rare. This 1-year, retrospective study was designed to assess the incidence and clinical determinants of IMI in centers in five countries (Thailand, Taiwan, Singapore, China, India). Patients treated in a single year (2012) were identified through discharge diagnoses, microbiology, and histopathology logs, and entered based on published definitions of IMI. A total of 155 cases were included (median age 54 years; 47.7% male)...
May 19, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
https://www.readbyqxmd.com/read/28523099/identification-of-new-flt3-inhibitors-that-potently-inhibit-aml-cell-lines-via-an-azo-click-it-staple-it-approach
#13
Xiaochu Ma, Jie Zhou, Changhao Wang, Brandon Carter-Cooper, Fan Yang, Elizabeth Larocque, Jonathan Fine, Genichiro Tsuji, Gaurav Chopra, Rena G Lapidus, Herman O Sintim
Acute myeloid leukemia (AML) is an aggressive malignancy with only a handful of therapeutic options. About 30% of AML patients harbor mutated FLT3 kinase, and thus, this cancer-driver has become a hotly pursued AML target. Herein we report a new class of FLT3 inhibitors, which potently inhibit the proliferation of acute myeloid leukemia (AML) cells at nanomolar concentrations.
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28522575/amplification-of-mixed-lineage-leukemia-gene-perturbs-hematopoiesis-and-cooperates-with-partial-tandem-duplication-to-induce-acute-myeloid-leukemia
#14
Bon Ham Yip, Chiou Tsun Tsai, Jayant K Rane, Winston Vetharoy, Eduardo Anguita, Shuo Dong, Michael A Caligiuri, Chi Wai Eric So
No abstract text is available yet for this article.
May 18, 2017: Haematologica
https://www.readbyqxmd.com/read/28522571/flt3-and-flt3-itd-phosphorylate-and-inactivate-the-cyclin-dependent-kinase-inhibitor-p27kip1-in-acute-myeloid-leukemia
#15
Ines Peschel, Silvio R Podmirseg, Martin Taschler, Justus Duyster, Katharina S Götze, Heinz Sill, David Nachbaur, Heidelinde Jäkel, Ludger Hengst
p27Kip1 can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. We observed that FLT3 and FLT3-ITD can directly bind and selectively phosphorylate p27 on this residue. Inhibition of FLT3-ITD in cell lines strongly reduced p27 tyrosine 88 phosphorylation and resulted in increased p27 levels and cell cycle arrest. Subsequent analysis revealed the presence of tyrosine 88 phosphorylated p27 in primary patient samples...
May 18, 2017: Haematologica
https://www.readbyqxmd.com/read/28521633/cd30-expression-in-pediatric-neoplasms-study-of-585-cases
#16
Jinjun Cheng, Haiqing Zhu, John Kim Choi
CD30 is a member of the tumor necrosis factor receptor superfamily, member 8 (TNFRSF8), and its normal expression is restricted to activated T and B cells. In tumor cells, CD30 expression is most commonly associated with lymphoid malignancies (Hodgkin and non-Hodgkin lymphomas) and is a therapeutic target using anti-CD30 antibody. CD30 expression has been reported also in mostly adult non-lymphoid malignancies, raising the possibility of CD30-targeted therapy for additional tumors. In this study, we examined the incidence of CD30 expression in 251 hematopoietic and 334 non-hematopoietic cases of pediatric tumors...
June 2017: Pediatric and Developmental Pathology
https://www.readbyqxmd.com/read/28521413/chromosome-t-7-11-p15-p15-translocation-in-acute-myeloid-leukemia-coexisting-with-multilineage-dyspoiesis-and-mutations-in-nras-and-wt1-a-case-report-and-literature-review
#17
Jingke Yang, Xiaodong Lyu, Xinghu Zhu, Xiangguang Meng, Wenli Zuo, Hao Ai, Mei Deng
The chromosomal translocation t(7;11)(p15;p15) and the resulting nucleoporin 98-homeobox A9 (NUP98-HOXA9) gene fusion is rare but recurrent genetic abnormity in acute myeloid leukemia (AML). The present study describes a case of AML plus maturation (-M2) with multilineage dyspoiesis in a 30-year-old male in whom a 46,XY,t(7;11)(p15;p15) karyotype was detected through chromosome analysis. Subsequent molecular and sequencing analysis demonstrated a NUP98-HOXA9 fusion gene with a type I fusion between NUP98 exon 12 and HOXA9 exon 1b, and mutations in neuroblastoma V-Ras oncogene homolog and Wilms tumor 1...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28518151/disulfiram-copper-selectively-eradicates-aml-leukemia-stem-cells-in-vitro-and-in-vivo-by-simultaneous-induction-of-ros-jnk-and-inhibition-of-nf-%C3%AE%C2%BAb-and-nrf2
#18
Bing Xu, Shiyun Wang, Rongwei Li, Kai Chen, Lingli He, Manman Deng, Vinodh Kannappan, Jie Zha, Huijuan Dong, Weiguang Wang
Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28516957/asxl2-is-essential-for-haematopoiesis-and-acts-as-a-haploinsufficient-tumour-suppressor-in-leukemia
#19
Jean-Baptiste Micol, Alessandro Pastore, Daichi Inoue, Nicolas Duployez, Eunhee Kim, Stanley Chun-Wei Lee, Benjamin H Durham, Young Rock Chung, Hana Cho, Xiao Jing Zhang, Akihide Yoshimi, Andrei Krivtsov, Richard Koche, Eric Solary, Amit Sinha, Claude Preudhomme, Omar Abdel-Wahab
Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28516360/gilteritinib-a-flt3-axl-inhibitor-shows-antileukemic-activity-in-mouse-models-of-flt3-mutated-acute-myeloid-leukemia
#20
Masamichi Mori, Naoki Kaneko, Yoko Ueno, Masaki Yamada, Ruriko Tanaka, Rika Saito, Itsuro Shimada, Kenichi Mori, Sadao Kuromitsu
Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML...
May 17, 2017: Investigational New Drugs
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