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JOURNAL ARTICLE
Peter W Jurutka, Orsola di Martino, Sabeeha Reshi, Sanchita Mallick, Michael A Sausedo, Grant A Moen, Isaac J Lee, Dominic J Ivan, Tyler D Krall, Samuel J Peoples, Anthony Perez, Lucas Tromba, Anh Le, Iraj Khadka, Ryan Petros, Brianna M Savage, Eleine Salama, Jakline Salama, Joseph W Ziller, Youngbin Noh, Ming-Yue Lee, Wei Liu, John S Welch, Pamela A Marshall, Carl E Wagner
Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene ( 1 ). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group...
December 19, 2022: International Journal of Molecular Sciences
#22
JOURNAL ARTICLE
Li Gao, Jun Lu, Jie Li, Yixin Hu, Ye Lu, Weiwei Du, Shaoyan Hu
We present a patient with acute megakaryoblastic leukemia (AMKL) harboring KMT2A-MLLT3 that converted to T cell acute lymphoblastic leukemia (T-ALL) at her fourth relapse. A 4-year-old girl developed AMKL with multiple swollen lymph nodes. She exhibited several recurrences in the bone marrow and died of septic shock after her fourth relapse. Bone marrow cells at the initial diagnosis and at all four relapses had the same KMT2A-MLLT3 fusion transcript. She also developed a somatic mutation (c.7177C > T p...
December 6, 2022: International Journal of Hematology
#23
JOURNAL ARTICLE
Omar Sepúlveda-Robles, Elva Jiménez-Hernández, Victoria Domínguez-Catzín, Eber Gómez-Flores, Jorge Alfonso Martín-Trejo, Janet Flores-Lujano, José Refugio Torres-Nava, Juan Carlos Núñez-Enríquez, Marlon De Ita, Aurora Medina-Sanson, Minerva Mata-Rocha, Blanca Angelica Morales-Castillo, Juan Carlos Bravata-Alcántara, Alan Steve Nájera-Cortés, Norberto Sánchez-Escobar, José Gabriel Peñaloza-Gonzalez, Rosa Martha Espinosa-Elizondo, Luz Victoria Flores-Villegas, Raquel Amador-Sanchez, Darío Orozco-Ruiz, Maria Luisa Pérez-Saldívar, Martha Margarita Velázquez-Aviña, Laura Elizabeth Merino-Pasaye, Karina Anastacia Solís-Labastida, Ana Itamar González-Ávila, Jessica Denisse Santillán-Juárez, Vilma Carolina Bekker-Méndez, Silvia Jiménez-Morales, Angélica Rangel-López, Haydeé Rosas-Vargas, Juan Manuel Mejía-Aranguré
BACKGROUND: The distribution of RUNX1-RUNXT1 , PML-RARA , CBFB-MYH11 , BCR-ABL1p210 , and KMT2A-MLLT3 in the pediatric population with acute myeloid leukemia (AML) in many countries of Latin America is largely unknown. Therefore, we aimed to investigate the frequency of these fusion genes in children with de novo AML from Mexico City, which has one of the highest incidence rates of acute leukemia in the world. Additionally, we explored their impact in mortality during the first year of treatment...
2022: Frontiers in Pediatrics
#24
JOURNAL ARTICLE
Xin-Xin Liu, Xin-An Pan, Meng-Ge Gao, Jun Kong, Hao Jiang, Ying-Jun Chang, Xiao-Hui Zhang, Yu Wang, Kai-Yan Liu, Zhong Chen, Xiao-Su Zhao, Xiao-Jun Huang
INTRODUCTION: AML patients with KMT2A-MLLT3 and other 11q23 abnormalities belong to the intermediate and high-risk level groups, respectively. Whether the poor prognostic value of Ecotropic Viral Integration site-1 (EVI1) overexpression suits either the subtypes of KMT2A-MLLT3 or Non-KMT2A-MLLT3 AML patients (intermediate and high risk group) needs to be further investigated. METHODS: We retrospectively analyzed the clinical characteristics of 166 KMT2A-r and KMT2A-PTD AML patients...
November 10, 2022: International Journal of Laboratory Hematology
#25
JOURNAL ARTICLE
Paola G Gonçalves, Rui M Reis, Lucas T Bidinotto
BACKGROUND/AIM: Deletions in chr9p22.1-21.3 locus have been related to the development of several types of cancer, mainly due to the presence of CDKN2A and CDKN2B genes. However, there are several other genes in the region with potential importance in tumorigenesis. We, therefore, aimed to analyze in silico the potential prognostic significance of alterations in copy number and expression of genes present in the chr9p22.1-21.3 locus in 33 TCGA datasets (approximately 10,000 patients)...
November 2022: Anticancer Research
#26
JOURNAL ARTICLE
Beibei Yu, Yunze Tian, Yongfeng Zhang, Boqiang Lv, Jianzhong Li, Shouping Gong
Ischemic stroke (IS) is a disease characterized by rapid progression and high mortality and disability rates. Its pathophysiological process is inseparable from immune dysfunction. Recently, chromatin regulators (CRs) have been described as a class of enzymes that can recognize, form, and maintain the epigenetic state of an organism, and are closely associated with immune regulation. Nevertheless, the role of CR-related genes in IS has not been fully elucidated. In this study, seven CR-related immune biomarkers in the GSE58294 and GSE22255 datasets were identified by combining differential gene expression analysis, weighted correlation network analysis, and single sample gene set enrichment analysis...
2022: Frontiers in Genetics
#27
JOURNAL ARTICLE
Tomoya Isobe, Masatoshi Takagi, Aiko Sato-Otsubo, Akira Nishimura, Genta Nagae, Chika Yamagishi, Moe Tamura, Yosuke Tanaka, Shuhei Asada, Reina Takeda, Akiho Tsuchiya, Xiaonan Wang, Kenichi Yoshida, Yasuhito Nannya, Hiroo Ueno, Ryo Akazawa, Itaru Kato, Takashi Mikami, Kentaro Watanabe, Masahiro Sekiguchi, Masafumi Seki, Shunsuke Kimura, Mitsuteru Hiwatari, Motohiro Kato, Shiro Fukuda, Kenji Tatsuno, Shuichi Tsutsumi, Akinori Kanai, Toshiya Inaba, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Rishi S Kotecha, Mark N Cruickshank, Fumihiko Ishikawa, Tomohiro Morio, Mariko Eguchi, Takao Deguchi, Nobutaka Kiyokawa, Yuki Arakawa, Katsuyoshi Koh, Yuki Aoki, Takashi Ishihara, Daisuke Tomizawa, Takako Miyamura, Eiichi Ishii, Shuki Mizutani, Nicola K Wilson, Berthold Göttgens, Satoru Miyano, Toshio Kitamura, Susumu Goyama, Akihiko Yokoyama, Hiroyuki Aburatani, Seishi Ogawa, Junko Takita
KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5)...
August 30, 2022: Nature Communications
#28
JOURNAL ARTICLE
Jinquan Wen, Min Zhou, Yali Shen, Yueting Long, Yuxia Guo, Lin Song, Jianwen Xiao
BACKGROUND: The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70-75% of infants, 5-6% of children and 10-15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. METHODS: A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group...
August 6, 2022: BMC Cancer
#29
JOURNAL ARTICLE
Lene Karlsson, Charlotte Guldborg Nyvold, Anastasia Soboli, Pegah Johansson, Lars Palmqvist, Anne Tierens, Henrik Hasle, Birgitte Lausen, Ólafur Gisli Jónsson, Gitte Wulff Jürgensen, Lene Hyldahl Ebbesen, Jonas Abrahamsson, Linda Fogelstrand
INTRODUCTION: Analysis of measurable residual disease (MRD) is increasingly being implemented in the clinical care of children and adults with acute myeloid leukaemia (AML). However, MRD methodologies differ and discordances in results lead to difficulties in interpretation and clinical decision-making. The aim of this study was to compare results from reverse transcription quantitative polymerase chain reaction (RT-qPCR) and multiparameter flow cytometry (MFC) in childhood AML and describe the kinetics of residual leukaemic burden during induction treatment...
August 2, 2022: International Journal of Laboratory Hematology
#30
JOURNAL ARTICLE
Maddalena Benetton, Pietro Merli, Christiane Walter, Maria Hansen, Ambra Da Ros, Katia Polato, Claudia Tregnago, Jonas Abrahamsson, Luisa Strocchio, Edwin Sonneveld, Linda Fogelstrand, Nils Von Neuhoff, Dirk Reinhardt, Henrik Hasle, Martina Pigazzi, Franco Locatelli
Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22) RUNX1::RUNX1T1 , or inv(16)(p13q22) CBFB::MYH11 , or t(9;11)(p21;q23) KMT2A::MLLT3, or FLT3 -ITD genetic markers...
June 28, 2022: Biomedicines
#31
JOURNAL ARTICLE
Francois Emile Mercier, Jiantao Shi, David Brian Sykes, Toshihiko Oki, Maja Jankovic, Cheuk Him Man, Youmna Sami Kfoury, Elizabeth Miller, Shutao He, Alexander Zhu, Radovan Vasic, John Doench, Alexandre Orthwein, Franziska Michor, David T Scadden
Genome-wide CRISPR screens have been extremely useful to identify therapeutic targets in diverse cancers, by defining genes that are essential for malignant growth. However, most CRISPR screens were performed in vitro and thus cannot identify genes that are essential for interactions with the microenvironment in vivo. Here, we report genome-wide CRISPR screens in two in vivo murine models of AML driven by the KMT2A/MLLT3 fusion or by the constitutive co-expression of Hoxa9 and Meis1. Secondary validation using a focused library identified 72 genes specifically essential for leukemic growth in vivo, including components of the MHC class I complex, Cd47, complement receptor Cr1l, and the beta-4-galactosylation pathway...
July 6, 2022: Blood Advances
#32
JOURNAL ARTICLE
Lin Xiao, Mawar Karsa, Emma Ronca, Angelika Bongers, Angelika Kosciolek, Ali El-Ayoubi, Jezrael L Revalde, Janith A Seneviratne, Belamy B Cheung, Laurence C Cheung, Rishi S Kotecha, Andrea Newbold, Stefan Bjelosevic, Greg M Arndt, Richard B Lock, Ricky W Johnstone, Andrei V Gudkov, Katerina V Gurova, Michelle Haber, Murray D Norris, Michelle J Henderson, Klaartje Somers
Rearrangements of the Mixed Lineage Leukemia ( MLL/KMT2A ) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models...
2022: Frontiers in Oncology
#33
Koji Nakajima, Hirohito Kubota, Itaru Kato, Kiyotaka Isobe, Hiroo Ueno, Kagehiro Kozuki, Kuniaki Tanaka, Naoko Kawabata, Takashi Mikami, Kosuke Tamefusa, Ritsuo Nishiuchi, Satoshi Saida, Katsutsugu Umeda, Hidefumi Hiramatsu, Souichi Adachi, Junko Takita
Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A-rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A-MLLT3-rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A-MLLT3-rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre-post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia...
July 2022: Cancer Science
#34
JOURNAL ARTICLE
Giuseppe Germano, Patrizia Porazzi, Carolyn A Felix
BACKGROUND: MLLT3 (AF9) is a nuclear transcription factor crucial for hematopoietic stem cell and progenitor cell maintenance, but its role during embryonic hematopoiesis remains uncertain. Here, we examine the role of mllt3 in developmental hematopoiesis during embryogenesis using zebrafish. RESULTS: Cloning, sequencing, phylogenetic, and synteny analyses showed high evolutionary conservation between important functional domains of the zebrafish orthologue of mllt3 and MLLT3 in humans...
October 2022: Developmental Dynamics
#35
JOURNAL ARTICLE
Vincenzo Calvanese, Sandra Capellera-Garcia, Feiyang Ma, Iman Fares, Simone Liebscher, Elizabeth S Ng, Sophia Ekstrand, Júlia Aguadé-Gorgorió, Anastasia Vavilina, Diane Lefaudeux, Brian Nadel, Jacky Y Li, Yanling Wang, Lydia K Lee, Reza Ardehali, M Luisa Iruela-Arispe, Matteo Pellegrini, Ed G Stanley, Andrew G Elefanty, Katja Schenke-Layland, Hanna K A Mikkola
The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites1 . Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1+ HOXA9+ MLLT3+ MECOM+ HLF+ SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the aorta-gonad-mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks...
April 2022: Nature
#36
JOURNAL ARTICLE
Belinda S Schmalzbauer, Teresemary Thondanpallil, Gerwin Heller, Alessia Schirripa, Clio-Melina Sperl, Isabella M Mayer, Vanessa M Knab, Sofie Nebenfuehr, Markus Zojer, André C Mueller, Frédéric Fontaine, Thorsten Klampfl, Veronika Sexl, Karoline Kollmann
Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukaemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase-dependent and kinase-independent effects, have been suggested as an alternative therapeutic option. We show that the efficacy of the CDK6-specific protein degrader BSJ-03-123 varies among AML subtypes and depends on the low expression of the INK4 proteins p16INK4A and p18INK4C ...
March 18, 2022: Cancers
#37
JOURNAL ARTICLE
Sergej Konoplev, Xiaoqiong Wang, Guilin Tang, Shaoying Li, Wei Wang, Jie Xu, Sherry A Pierce, Fuli Jia, Jeffrey L Jorgensen, Farhad Ravandi, Ghayas C Issa, L Jeffrey Medeiros, Sa A Wang
BACKGROUND: Acute myeloid leukemia (AML) with KMT2A (MLL) rearrangement is known for monocytic or myelomonocytic differentiation, but the full immunophenotypic spectrum and dynamic changes of the immunophenotype in this genetically defined disease have not been systematically studied. METHODS: We reviewed the immunophenotype, karyotype, and mutations at the time of initial diagnosis and relapse of adults with AML with KMT2A rearrangement in our institution between 2007 and 2020...
March 2022: Cytometry. Part B, Clinical Cytometry
#38
JOURNAL ARTICLE
Holly E Berg, Patricia T Greipp, Linda B Baughn, Corey P Falcon, Courtney C Jackson, Jess F Peterson
KMT2A gene rearrangements are a major oncogenic driver in multiple hematologic neoplasms. Apart from t(9;11)(p21;q23) (KMT2A/MLLT3) in acute myeloid leukemia (AML), KMT2A gene rearrangements are considered to convey high risk and poor overall survival. Herein, we report a case of a 7 year old boy with newly diagnosed AML and a cryptic KMT2A/AFDN gene fusion resulting from a 5'KMT2A insertional event. The results of conventional chromosome studies revealed trisomy 8 in all 20 metaphases, with normal-appearing chromosomes 6 and 11...
July 4, 2022: Laboratory Medicine
#39
JOURNAL ARTICLE
Zhenqiu Liu, Vladimir S Spiegelman, Hong-Gang Wang
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease in both children and adults. Although it is well-known that adult and pediatric AMLs are genetically distinct diseases, the driver genes for high-risk pediatric and adult AMLs are still not fully understood. Particularly, the interactions between RNA binding proteins (RBPs) and noncoding RNAs (ncRNAs) for high-risk AMLs have not been explored. AIM: To identify RBPs and noncoding RNAs (ncRNAs) that are the master regulators of high-risk AML...
December 4, 2021: Cancer reports
#40
JOURNAL ARTICLE
Peter W Jurutka, Orsola di Martino, Sabeeha Reshi, Sanchita Mallick, Zhela L Sabir, Lech J P Staniszewski, Ankedo Warda, Emma L Maiorella, Ani Minasian, Jesse Davidson, Samir J Ibrahim, San Raban, Dena Haddad, Madleen Khamisi, Stephanie L Suban, Bradley J Dawson, Riley Candia, Joseph W Ziller, Ming-Yue Lee, Chang Liu, Wei Liu, Pamela A Marshall, John S Welch, Carl E Wagner
Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene ( 1 ), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system...
November 16, 2021: International Journal of Molecular Sciences
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