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NPM1 mutation

Andrew D Kelly, Jozef Madzo, Priyanka Madireddi, Patricia Kropf, Charly R Good, Jaroslav Jelinek, Jean-Pierre J Issa
Acute myeloid leukemia (AML) often harbors mutations in epigenetic regulators, and also has frequent DNA hypermethylation, including the presence of CpG island methylator phenotypes (CIMPs). Although global hypomethylation is well known in cancer, the question of whether distinct demethylator phenotypes (DMPs) exist remains unanswered. Using Illumina 450k arrays for 194 patients from The Cancer Genome Atlas, we identified two distinct DMPs by hierarchical clustering: DMP.1 and DMP.2. DMP.1 cases harbored mutations in NPM1 (94%), FLT3 (71%) and DNMT3A (61%)...
March 7, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Jingyi Li, Jie Xu, Lynne V Abruzzo, Guilin Tang, Shaoying Li, M James You, Gary Lu, Elias J Jabbour, Qi Deng, Carlos E Bueso-Ramos, L Jeffrey Medeiros, C Cameron Yin
We describe the clinical, morphologic, immunophenotypic and molecular genetic features of 15 cases of acute myeloid leukemia (AML) with t(4;12)(q12;p13). There were 9 men and 6 women, with a median age of 50 years (range, 17-76). Most patients had hypercellular bone marrow with a median blast count of 58% and multilineage dysplasia. Flow cytometry analysis showed myeloid lineage with blasts positive for CD13, CD33, CD34, CD38, CD117 and HLA-DR. Interestingly, aberrant CD7 expression was detected in 12/14 cases, and myeloperoxidase was either negative (3/15) or positive in only a small subset of the blasts (12/15)...
February 16, 2018: Oncotarget
Y Liu, T Lei, Y Shi, X Y Wang, M L Sun, W X Fan, Z N Zhang, M Jiang
Objective: To explore the expression and significance of Set gene in Acute myeloid leukemia (AML) patients , and to analyze its effect for the prognosis of AML. Methods: The level of Set gene expression was detected by real-time PCR in 59 AML patients and 20 heathy people. The mutations in C-kit 8/17 gene, NPM1 gene and FLT3-TKD/ITD gene in 59 AML patients were detected by direct sequencing. Results: The level of Set gene expression[1.41(0.41-3.31)]was significantly higher in 59 AML patients.The expression of Set gene was correlated with the percentage of marrow blasts and CR in AML patients ( P =0...
March 6, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Phuong L Trinh, Yen Pham
Numerous studies have identified Nucleophosmin 1 ( NPM1 ) and Fms -like tyrosine kinase 3 ( FLT3 ) as the most frequently mutated genes in Acute Myeloid Leukemia (AML) patients. Mutations occurring in these genes, including NPM1+4 (tetranucleotide insertions), FLT3-ITD (internal tandem duplications), and FLT3-TKD (tyrosine kinase domain point mutations) account for approximately 80% of all mutations found in normal karyotype AML (AML-NK) cases. Different methods have been established to detect the three listed mutations, in which, PCR-based techniques are the most widely used due to their efficiency...
January 2018: Annals of Clinical and Laboratory Science
Sarah Bertoli, Muriel Picard, Emilie Bérard, Emmanuel Griessinger, Clément Larrue, Pierre-Luc Mouchel, François Vergez, Suzanne Tavitian, Edwige Yon, Jean Ruiz, Eric Delabesse, Isabelle Luquet, Laetitia Karine Linares, Estelle Saland, Martin Carroll, Gwenn Danet-Desnoyers, Audrey Sarry, Françoise Huguet, Jean-Emmanuel Sarry, Christian Récher
Patients with acute myeloid leukemia and a high white blood cell count are at increased risk for early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50x109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone...
March 8, 2018: Haematologica
Jonathan Canaani, Myriam Labopin, Xiao-Jun Huang, William Arcese, Fabio Ciceri, Didier Blaise, Giuseppe Irrera, Lucia Lopez Corral, Benedetto Bruno, Stella Santarone, Maria Teresa Van Lint, Antonin Vitek, Jordi Esteve, Mohamad Mohty, Arnon Nagler
Acute myeloid leukemia (AML) patients harboring the FLT3-ITD mutation are considered a high risk patient subset preferentially allocated for allogeneic stem cell transplantation in first remission. Whether FLT3-ITD retains a prognostic role in haploidentical stem cell transplantation (haplo-SCT) is unknown. To analyze the prognostic impact of FLT3-ITD in haplo-SCT, we performed a retrospective analysis of the multicenter registry of the acute leukemia working party of the European Society for Blood and Marrow Transplantation...
March 2, 2018: American Journal of Hematology
Zhiheng Cheng, Kai Hu, Lei Tian, Yifeng Dai, Yifan Pang, Wei Cui, Hongmian Zhao, Tong Qin, Yu Han, Ning Hu, Li Chen, Chao Wang, Yijie Zhang, Depei Wu, Xiaoyan Ke, Jinlong Shi, Lin Fu
The mutational spectrum and molecular characteristics of acute myelomonocytic lineage leukemia, namely acute myeloid leukemia (AML) French-American-British (FAB) subtypes M4 and M5, are largely unknown. In order to explore the mutational spectrum and prognostic factors of FAB-M4 and -M5, next-generation sequencing (NGS) was performed to screen for mutated genes and fusion genes relevant to the pathogenesis of AML. Of the 63 patients enrolled in the study, 60% had more than three mutated genes. NPM1 had the highest mutation frequency, followed by DNMT3A, FLT3, NRAS, RUNX1, and TET2...
February 28, 2018: Cancer Gene Therapy
Maria Chiara Fontana, Giovanni Marconi, Jelena D Milosevic Feenstra, Eugenio Fonzi, Cristina Papayannidis, Andrea Ghelli Luserna di Rorá, Antonella Padella, Vincenza Solli, Eugenia Franchini, Emanuela Ottaviani, Anna Ferrari, Carmen Baldazzi, Nicoletta Testoni, Ilaria Iacobucci, Simona Soverini, Torsten Haferlach, Viviana Guadagnuolo, Lukas Semerad, Michael Doubek, Michael Steurer, Zdenek Racil, Stefania Paolini, Marco Manfrini, Michele Cavo, Giorgia Simonetti, Robert Kralovics, Giovanni Martinelli
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix® ) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients...
February 23, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Yann Ferret, Nicolas Boissel, Nathalie Helevaut, Jordan Madic, Olivier Nibourel, Alice Marceau-Renaut, Maxime Bucci, Sandrine Geffroy, Karine Celli-Lebras, Sylvie Castaigne, Xavier Thomas, Christine Terré, Hervé Dombret, Claude Preudhomme, Aline Renneville
Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of IDH1/2 mutations as targets for minimal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15-20% of acute myeloid leukemia and now represent druggable targets. We employed droplet digital PCR assays to quantify IDH1R132, IDH2R140, and IDH2R172 mutations on genomic DNA in 322 samples from 103 adult patients with primary IDH1/2 mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) -0701 or -0702 clinical trials...
February 22, 2018: Haematologica
Jie Peng, Bin Fu, Gan Fu, Xielan Zhao, Xiaolin Li, Fangping Chen
Acute myeloid leukemia (AML) is the most malignant myeloid disorder in adults. AML with mutated nucleophosmin (NPM1) is regarded as an independent leukemia subtype. According to previous studies, the role of NPM1 gene A mutation in AML has been well established; however, another major type, NPM1 gene B type mutation (NPM1 MutB) has been rarely reported. In the present study, we found that overexpression of NPM1 MutB enhanced the proliferation and invasion of THP-1 AML cells through the regulation of TIMP-2, MMP-2, Ang-1, c-myc and CCND1; led to no significant change of apoptosis rate with the absence of chemotherapy agents, while enhanced the chemosensitivity of THP-1 AML cells to chemotherapy agents DNR and Ara-C through the regulation of Bax, Bcl-2 and caspase-3...
October 1, 2017: Die Pharmazie
Jae-Sook Ahn, Hyeoung-Joon Kim, Yeo-Kyeoung Kim, Seung-Shin Lee, Seo-Yeon Ahn, Sung-Hoon Jung, Deok-Hwan Yang, Je-Jung Lee, Hee Jeong Park, Ja-Yeon Lee, Seung Hyun Choi, Chul Won Jung, Jun-Ho Jang, Hee Je Kim, Joon Ho Moon, Sang Kyun Sohn, Yoo Jin Lee, Jong-Ho Won, Sung-Hyun Kim, Zhaolei Zhang, TaeHyung Kim, Dennis Dong Hwan Kim
This study was performed to assess if a recently recommended genomic classification is predictive in patients with normal-karyotype (NK) acute myeloid leukemia (AML). A total of 393 patients were included. Analysis of genetic mutations was performed using targeted resequencing with an Illumina Hiseq 2000. We identified driver mutations across 40 genes, with one or more driver mutations identified in 95.7% of patients. The molecular subclassification was as follows: 34.6% patients (n = 136) with AML with the NPM1 mutation, 10...
January 12, 2018: Oncotarget
Piers Blombery, Kate Jones, Ken Doig, Georgina Ryland, Michelle McBean, Ella Thompson, Costas K Yannakou, David Westerman
CONTEXT: - Detection of measurable residual disease after therapy is an important predictor of outcome in acute myeloid leukemia. OBJECTIVE: - To investigate the feasibility of using next-generation sequencing (NGS) in the diagnostic laboratory to perform quantitative NPM1 mutation assessment using ultradeep (approximately 300 000×-500 000×) sequencing (NGS-q NPM1) as a method of assessing residual disease burden in patients with acute myeloid leukemia. DESIGN: - A flexible NGS-based assay for the detection and quantitation of NPM1 mutations was developed by polymerase chain reaction amplification of target DNA sequences, sequencing on an Illumina (San Diego, California) MiSeq, and analyzing data with an in-house-designed bioinformatic pipeline...
February 9, 2018: Archives of Pathology & Laboratory Medicine
Shinya Sato, Hidehiro Itonaga, Masataka Taguchi, Yasushi Sawayama, Daisuke Imanishi, Hideki Tsushima, Tomoko Hata, Yukiyoshi Moriuchi, Hiroyuki Mishima, Akira Kinoshita, Koh-Ichiro Yoshiura, Yasushi Miyazaki
In acute myeloid leukemia (AML), patients may harbor pre-leukemic hematopoietic stem cells (HSCs) containing some, but not all, of the mutations observed in the leukemic cells. These pre-leukemic HSCs may survive induction chemotherapy and contribute to AML relapse by obtaining additional mutations. We report here an acute monoblastic leukemia (AMoL) patient who later developed an unclassifiable myeloproliferative neoplasm (MPN-U). Whole-exome sequencing and cluster analysis demonstrated the presence of three distinct major clones during the clinical course: (1) an AMoL clone with ASXL1, CBL, and NPM1 somatic mutations, likely associated with the pathogenesis, and GATA2, SRSF2, and TET2 mutations, (2) an AMoL remission clone, with mutated GATA2, SRSF2, and TET2 only (possibly the founding clone (pre-leukemic HSC) that survived chemotherapy), (3) a small subclone which had JAK2 mutation during the AMoL remission, appearing at MPN-U manifestation with additional mutations...
February 7, 2018: International Journal of Hematology
Ya-Zhen Qin, Ting Zhao, Hong-Hu Zhu, Jing Wang, Jin-Song Jia, Yue-Yun Lai, Xiao-Su Zhao, Hong-Xia Shi, Yan-Rong Liu, Hao Jiang, Xiao-Jun Huang, Qian Jiang
BACKGROUND Acute myeloid leukemia with intermediate cytogenetic risk (ICR-AML) needs to be stratified. The abnormal gene expression might be prognostic, and its cutoff value for patient grouping is pivotal. MATERIAL AND METHODS Ecotropic viral integration site 1 (EVI1) transcripts were assessed in 191 adult ICR-AML patients at diagnosis who received chemotherapy only. MLL-PTD, WT1 transcript levels, FLT3-ITD, and NPM1 mutations were simultaneously evaluated, and 27 normal bone marrow samples were tested to define normal threshold...
February 6, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Jinghan Wang, Fenglin Li, Zhixin Ma, Mengxia Yu, Qi Guo, Jiansong Huang, Wenjuan Yu, Yungui Wang, Jie Jin
Ten-Eleven-Translocation 1 (TET1) plays a role in the DNA methylation process and gene activation. Recent reports suggest TET1 acts as an oncogene in leukemia development. However, the clinical relevance and biological insight of TET1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) is unknown. In this study, quantification of TET1 transcript by real-time quantitative PCR in bone marrow blasts was performed in 360 CN-AML patients. As a result, high TET1 expression was more common in M0/M1 morphology and genes of NPM1 mutations, and underrepresented in CEBPA double allele mutations in our AML patients...
January 31, 2018: EBioMedicine
Jina Bhattacharyya, Sukanta Nath, Kandarpa Kumar Saikia, Renu Saxena, Sudha Sazawal, Manash Pratim Barman, Dushyant Kumar
Acute Myeloid Leukaemia (AML) is one of the common forms of haematological malignancy in adults. We analysed the prevalence and clinical significance of FMS-like tyrosine kinase 3 (FLT3) and Nucleophosmin 1 (NPM1) mutations in AML patients of North East India. Co-prevalence and clinical significance of three recurrent chromosomal translocations namely t(15; 17), t(8; 21), t(16; 16) and expression of epidermal growth factor receptor (EGFR), flow markers were also documented and co-related with disease progress...
January 2018: Indian Journal of Hematology & Blood Transfusion
Yasuhiko Harada, Yasunobu Nagata, Rika Kihara, Yuichi Ishikawa, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Shinichi Kobayashi, Kunio Kitamura, Emiko Sakaida, Makoto Onizuka, Akihiro Takeshita, Fumihiro Ishida, Hitoshi Suzushima, Kenichi Ishizawa, Tomoki Naoe, Itaru Matsumura, Yasushi Miyazaki, Seishi Ogawa, Hitoshi Kiyoi
Many genetic alterations that are associated with the prognosis of acute myeloid leukemia (AML) have been identified, and several risk stratification systems based on the genetic status have been recommended. The European LeukemiaNet (ELN) first proposed the risk stratification system for AML in 2010 (ELN-2010), and recently published the revised system (ELN-2017). We validated the long-term prognosis and clinical characteristics of each ELN-2017 risk category in Japanese adult AML patients who were treated in the Japan Adult Leukemia Study Group (JALSG) AML-201 study...
March 2018: Leukemia Research
Hongjun Jin, Liyuan Yang, Lu Wang, Zailin Yang, Qian Zhan, Yao Tao, Qin Zou, Yuting Tang, Jingrong Xian, Shuaishuai Zhang, Yipei Jing, Ling Zhang
BACKGROUND: Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been recognized as a distinct leukemia entity in the 2016 World Health Organization (WHO) classification. The genetic events underlying oncogenesis in NPM1-mutated AML that is characterized by a normal karyotype remain unclear. Inositol polyphosphate 4-phosphatase type II (INPP4B), a new factor in the phosphoinositide-3 kinase (PI3K) pathway-associated cancers, has been recently found a clinically relevant role in AML...
January 17, 2018: Journal of Experimental & Clinical Cancer Research: CR
Akira Shimada, Yuka Iijima-Yamashita, Akio Tawa, Daisuke Tomizawa, Miho Yamada, Shiba Norio, Tomoyuki Watanabe, Takashi Taga, Shotaro Iwamoto, Kiminori Terui, Hiroshi Moritake, Akitoshi Kinoshita, Hiroyuki Takahashi, Hideki Nakayama, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Akiko Moriya Saito, Nobutaka Kiyokawa, Keizo Horibe, Yusuke Hara, Kentaro Oki, Yasuhide Hayashi, Shiro Tanaka, Souichi Adachi
Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis. We evaluated the results of the AML-05 study, in which all AMLFLT3-ITD patients were assigned to receive hematopoietic stem cell transplantation (HSCT) in the first remission (1CR). We also investigated the effects of additional genetic alterations on FLT3-ITD. The 5-year overall survival (OS) and event-free survival (EFS) rates among the 47 AMLFLT3-ITD patients were 42...
January 12, 2018: International Journal of Hematology
Olga K Weinberg, Christopher J Gibson, Traci M Blonquist, Donna Neuberg, Olga Pozdnyakova, Frank Kuo, Benjamin L Ebert, Robert P Hasserjian
Despite improvements in our understanding of the molecular basis of acute myeloid leukemia, the association between genetic mutations with morphologic dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow specimens from 168 patients with de novo acute myeloid leukemia; none of these patients had 2016 WHO Classification-defined cytogenetic abnormalities. We then performed targeted sequencing of diagnostic bone marrow aspirates for recurrent mutations associated with myeloid malignancies...
January 11, 2018: Haematologica
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