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NPM1 mutation

Dushyant Kumar, Anurag Mehta, Manoj Kumar Panigrahi, Sukanta Nath, Kandarpa Kumar Saikia
OBJECTIVE: Nucleophosmin-1 (NPM1) mutations have prognostic importance in acute myeloid leukemia (AML) patients with intermediate-risk karyotype at diagnosis. Approximately 30% of newly diagnosed cytogenetically normal AML (CN-AML) patients harbor NPM1 mutation in India. In this study we compared the efficiency of three molecular techniques in detecting NPM1 mutation in perepherial blood and bone marrow samples. MATERIALS AND METHODS: In a single centre cohort we analyzed 165 CN-AML bone marrow/peripheral blood for NPM1 mutation analysis...
November 13, 2017: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
A De Cola, M Franceschini, A Di Matteo, G Colotti, R Celani, E Clemente, R Ippoliti, A M Cimini, A C Dhez, B Vallée, F Raineri, I Cascone, D Destouches, V De Laurenzi, J Courty, L Federici
NPM1 is a multifunctional nucleolar protein implicated in several processes such as ribosome maturation and export, DNA damage response and apoptotic response to stress stimuli. The NPM1 gene is involved in human tumorigenesis and is found mutated in one third of acute myeloid leukemia patients, leading to the aberrant cytoplasmic localization of NPM1. Recent studies indicated that the N6L multivalent pseudopeptide, a synthetic ligand of cell-surface nucleolin, is also able to bind NPM1 with high affinity. N6L inhibits cell growth with different mechanisms and represents a good candidate as a novel anticancer drug for a number of malignancies of different histological origin...
October 27, 2017: Cancer Letters
Christiane Walter, Christian Pozzorini, Katarina Reinhardt, Robert Geffers, Zhenyu Xu, Dirk Reinhardt, Nils von Neuhoff, Helmut Hanenberg
BACKGROUND: The small portion of leukemic stem cells (LSCs) in acute myeloid leukemia (AML) present in children and adolescents is often masked by the high background of AML blasts and normal hematopoietic cells. The aim of the current study was to establish a simple workflow for reliable genetic analysis of single LSC-enriched blasts from pediatric patients. PROCEDURE: For three AMLs with mutations in nucleophosmin 1 and/or fms-like tyrosine kinase 3, we performed whole genome amplification on sorted single-cell DNA followed by whole exome sequencing (WES)...
November 1, 2017: Pediatric Blood & Cancer
Dushyant Kumar, Anurag Mehta, Manoj Kumar Panigrahi, Sukanta Nath, Kandarpa Kumar Saikia
OBJECTIVE/BACKGROUND: In the absence of high-risk cytogenetic, DNMT3A mutation status has an impact on outcome in the presence of FLT3 and/or NPM1. In this study, we focus on the features and effect of DNMT3A (R882) mutation in acute myeloid leukemia (AML) in the presence or absence of NPM1 and FLT3 mutations. METHODS: A total of 174 cytogenetically normal (CN)-AML cases were analyzed for NPM1, FLT3, and DNMT3A mutations. For NPM1 mutation detection, we used the pyrosequencing technique; for FLT3 mutations, polymerase chain reaction and RFLP with ECO-RV techniques were used, and for DNMT3A mutation analysis, we used Sanger sequencing and RFLP techniques...
October 18, 2017: Hematology/oncology and Stem Cell Therapy
Brunangelo Falini, Paolo Sportoletti
No abstract text is available yet for this article.
October 26, 2017: Blood
Sze-Hwei Lee, Yu-Chiao Chiu, Yi-Hung Li, Chien-Chin Lin, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien
DOCK family genes encode evolutionarily conserved guanine nucleotide exchange factors for Rho GTPase involving multiple biological functions. Yet the patterns and prognostic significance of their expression in acute myeloid leukemia (AML) remain unexplored. Here we analyzed the expression patterns of 11 DOCK family genes in AML cells based on the array data of 347 patients from our cohort and several other published datasets. We further focused on the implications of the expression of DOCK1 since it was the only one in DOCK family to be associated with survival...
September 22, 2017: Oncotarget
Samuel Sidi, Lisa Bouchier-Hayes
Despite being frequently mutated or deregulated in acute myeloid leukemia (AML) and many other cancers, the mechanisms by which nucleophosmin (NPM1) regulates oncogenesis remain elusive. We found that NPM1 plays a direct and conserved role in DNA damage-induced assembly of the PIDDosome complex, the activating platform for caspase-2. This function is carried in the nucleolus and is essential for caspase-2-mediated apoptosis in response to a variety of DNA injuries.
2017: Molecular & Cellular Oncology
Yachiyo Kuwatsuka, Daisuke Tomizawa, Rika Kihara, Yasunobu Nagata, Norio Shiba, Yuka Iijima-Yamashita, Akira Shimada, Takao Deguchi, Hayato Miyachi, Akio Tawa, Takashi Taga, Akitoshi Kinoshita, Hideki Nakayama, Nobutaka Kiyokawa, Akiko Moriya Saito, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Yasushi Miyazaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Shinichi Kobayashi, Kunio Kitamura, Emiko Sakaida, Seishi Ogawa, Tomoki Naoe, Yasuhide Hayashi, Keizo Horibe, Atsushi Manabe, Shuki Mizutani, Souichi Adachi, Hitoshi Kiyoi
Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years...
October 12, 2017: International Journal of Hematology
Rachna Khera, Faiq Ahmed, Manasi Mundada, Lavanya Nambaru, Sudha S Murthy, Sandhya Devig, Senthil J Rajappa, Krishna Mohan Mallavarapu, A Santa, Pavan Kumar
OBJECTIVE: Molecular genetic analysis of FLT3, NPM1, and CEBPA is already the standard of care in patients with acute myeloid leukaemia (AML) and represents the most frequent genetic alterations and important diagnostic and prognostic indicators. This study was undertaken to determine the frequency of FLT3 and NPM1 gene mutations in our institution and to characterize the association between gene mutations and haematological parameters as well as immunophenotypic features. MATERIAL AND METHOD: Morphological, haematological and immunophenotypic characteristics of NPM1 and FLT3 mutations in 126 patients of de novo AML including adults and children were studied...
October 6, 2017: Türk Patoloji Dergisi
Daisuke Tomizawa
Both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are common malignant diseases in adolescents and young adults (AYAs). Recent advances in genomic studies have helped us understand the biological nature of acute leukemia in AYAs; higher frequency of Ph-like ALL and rearrangements in DUX4, ERG, MEF2D, and ZNF384 genes in AYAs with ALL and higher frequency of FLT3-ITD, NPM1, IDH1/2, DNMT3A, ASXL1, TET2, and CEBPA mutations in AYAs with AML than that in children. The pediatric-inspired regimen has become a standard treatment approach for AYAs with ALL, but optimal treatment strategy for AYAs with AML is not yet established to date...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Susanne Hirsch, Tamara J Blätte, Sarah Grasedieck, Sibylle Cocciardi, Arefeh Rouhi, Mojca Jongen-Lavrencic, Peter Paschka, Jan Krönke, Verena I Gaidzik, Hartmut Döhner, Richard F Schlenk, Florian Kuchenbauer, Konstanze Döhner, Anna Dolnik, Lars Bullinger
In acute myeloid leukemia there is growing evidence for splicing pattern deregulation, including differential expression of linear splice isoforms of the commonly mutated gene nucleophosmin (NPM1). In this study, we detect circular RNAs of NPM1 and quantify circRNA hsa_circ_0075001 in a cohort of NPM1 wildtype and mutated acute myeloid leukemia (n=46). Hsa_circ_0075001 expression correlates positively with total NPM1 expression, but is independent of the NPM1 mutational status. High versus low hsa_circ_0075001 expression defines patient subgroups characterized by distinct gene expression patterns, such as lower expression of components of the Toll-like receptor signaling pathway in high hsa_circ_0075001 expression cases...
September 29, 2017: Haematologica
K Heidrich, C Thiede, K Schäfer-Eckart, N Schmitz, W E Aulitzky, A Krämer, W Rösler, M Hänel, H Einsele, C D Baldus, R U Trappe, F Stölzel, J M Middeke, C Röllig, F Taube, M Kramer, H Serve, W E Berdel, G Ehninger, M Bornhäuser, J Schetelig
Background: The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) without FLT3-ITD, biallelic CEBPA-, or NPM1 mutations (here referred to as NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML) in first complete remission (CR1). Patients and methods: We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Sudha Sazawal, Neha Singh, Sonal Jain, Sunita Chhikara, Rekha Chaubey, Jina Bhattacharyya, Kandarpa Kr Saikia, Manoranjan Mahapatra, Renu Saxena
BACKGROUND: FLT3-ITD and NPM1 mutations are considered to be the major determinants of the patient response to therapy and outcome. The primary aim of this study was to establish the correlation between these molecular mutations and the clinico-hematologic parameters as well as the prognostic outcome of the Indian acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: This prospective study involved newly diagnosed nonpromyelocytic AML patients who had undergone complete diagnostic workup, including immunophenotyping, conventional cytogenetics and molecular analysis for NPM1 and FLT3-ITD mutation by reverse transcriptase polymerase chain reaction at presentation...
July 2017: Indian Journal of Pathology & Microbiology
Eunkyoung You, Young-Uk Cho, Seongsoo Jang, Eul-Ju Seo, Jung-Hee Lee, Je-Hwan Lee, Kyoo-Hyung Lee, Kyung-Nam Koh, Ho Joon Im, Jong Jin Seo, Young-Mi Park, Jong-Keuk Lee, Chan-Jeoung Park
Objectives: To evaluate the frequency and clinicopathologic characteristics of RUNX1 mutations, focusing on patients with acute myeloid leukemia not otherwise specified (AML NOS). Methods: Diagnostic samples from 219 patients with AML NOS were analyzed for RUNX1 mutations using standard polymerase chain reaction and direct sequencing. Results: Thirty-one RUNX1 mutations were detected in 33 (15.1%) patients. Mutations clustered in the Runt homology (61...
July 1, 2017: American Journal of Clinical Pathology
Thiago Rodrigo de Noronha, Miguel Mitne-Neto, Maria de Lourdes Chauffaille
Karyotype (KT) aberrations are important prognostic factors for acute myeloid leukemia (AML); however, around 50% of cases present normal results. Single nucleotide polymorphism array can detect chromosomal gains, losses or uniparental disomy that are invisible to KT, thus improving patients' risk assessment. However, when both tests are normal, important driver mutations can be detected by the use of next-generation sequencing (NGS). Fourteen adult patients with AML with normal cytogenetics were investigated by NGS for 19 AML-related genes...
September 18, 2017: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
A Di Matteo, M Franceschini, A Paiardini, A Grottesi, S Chiarella, S Rocchio, C Di Natale, D Marasco, L Vitagliano, C Travaglini-Allocatelli, L Federici
Nucleophosmin (NPM1) is a multifunctional nucleolar protein implicated in ribogenesis, centrosome duplication, cell cycle control, regulation of DNA repair and apoptotic response to stress stimuli. The majority of these functions are played through the interactions with a variety of protein partners. NPM1 is frequently overexpressed in solid tumors of different histological origin. Furthermore NPM1 is the most frequently mutated protein in acute myeloid leukemia (AML) patients. Mutations map to the C-terminal domain and lead to the aberrant and stable localization of the protein in the cytoplasm of leukemic blasts...
September 18, 2017: Oncogenesis
Ming-Yu Yang, Hui-Hua Hsiao, Yi-Chang Liu, Cheng-Ming Hsu, Sheng-Fung Lin, Pai-Mei Lin
BACKGROUND/AIM: Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established. This study aimed to examine mutation of LKB1 in AML and its clinical and pathological implications. PATIENTS AND METHODS: Eighty-five patients newly diagnosed with cytogenetically normal AML were analyzed using polymerase chain reaction followed by direct sequencing...
September 2017: In Vivo
Ting Si, Ying Lu, Fenglin Li, Lei Jiang, Renzhi Pei, Jeff X Zhou
Inhibin-β A (INHBA) is a ligand of the transforming growth factor β superfamily and associated with tumorigenesis and tumor progression in solid tumors. In this study, we investigated the expression levels and clinical significance of INHBA in acute myeloid leukemia (AML). The results showed that high expression of INHBA was significantly correlated with elderly age (>60 years) (p = .038), adverse cytogenetic risks (p = .034), negative NPM1 mutation (p = .016), positive FLT3 internal tandem duplications (p = ...
August 24, 2017: Leukemia & Lymphoma
Oliver M Dovey, Jonathan L Cooper, Annalisa Mupo, Carolyn S Grove, Claire Lynn, Nathalie Conte, Robert M Andrews, Suruchi Pacharne, Konstantinos Tzelepis, M S Vijayabaskar, Paul Green, Roland Rad, Mark Arends, Penny Wright, Kosuke Yusa, Allan Bradley, Ignacio Varela, George S Vassiliou
NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound Npm1(cA/+);Nras(G12D/+) or Npm1(cA);Flt3(ITD) share a number of features: Hox gene overexpression, enhanced self-renewal, expansion of hematopoietic progenitors, and myeloid differentiation bias...
October 26, 2017: Blood
Yong-Mei Zhu, Pan-Pan Wang, Jin-Yan Huang, Yun-Shuo Chen, Bing Chen, Yu-Jun Dai, Han Yan, Yi Hu, Wen-Yan Cheng, Ting-Ting Ma, Sai-Juan Chen, Yang Shen
BACKGROUND: Cytogenetic aberrations and gene mutations have long been regarded as independent prognostic markers in AML, both of which can lead to misexpression of some key genes related to hematopoiesis. It is believed that the expression level of the key genes is associated with the treatment outcome of AML. METHODS: In this study, we analyzed the clinical features and molecular aberrations of 560 newly diagnosed non-M3 AML patients, including mutational status of CEBPA, NPM1, FLT3, C-KIT, NRAS, WT1, DNMT3A, MLL-PTD and IDH1/2, as well as expression levels of MECOM, ERG, GATA2, WT1, BAALC, MEIS1 and SPI1...
August 22, 2017: Journal of Translational Medicine
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