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Zsuzsanna Gaál, Éva Oláh, László Rejtő, Ferenc Erdődi, László Csernoch
Histone deacetylase enzymes, confirmed to have important role in the pathogenesis of leukemia, are promising targets of epigenetic treatment. However, in acute myeloid leukemia, our knowledge on their expression levels is limited, and controversial data have been published about their potential oncogenic or tumorsuppressor properties in solid tumors. In our study, the expression levels of HDAC4 and SIRT6 were evaluated via Western blot analysis in 45 bone marrow samples (2 uninfiltrated and 43 concerned by different kinds of hematological malignancies), including 32 specimens obtained from patients with newly diagnosed AML...
October 20, 2016: Pathology Oncology Research: POR
Himalee S Sabnis, Heath L Bradley, Shweta Tripathi, Wen-Mei Yu, William Tse, Cheng-Kui Qu, Kevin D Bunting
Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism...
October 5, 2016: Leukemia Research
M Wu, M Hamaker, L Li, D Small, A S Duffield
The FMS-like tyrosine kinase-3 (FLT3) gene is the most commonly mutated gene in acute myeloid leukemia (AML), and patients carrying internal tandem duplication (ITD) mutations have a poor prognosis. Long-term inhibition of FLT3 activity in these patients has been elusive. To provide a more complete understanding of FLT3 biology, a mass spectroscopy-based screen was performed to search for FLT3-interacting proteins. The screen identified dedicator of cytokinesis 2 (DOCK2), which is a guanine nucleotide exchange factor for Rho GTPases, and its expression is limited to hematolymphoid cells...
October 17, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Anita Chopra, Sushant Soni, Haraprasad Pati, Dev Kumar, Rahul Diwedi, Deepak Verma, Garima Vishwakama, Sameer Bakhshi, Suman Kumar, Ajay Gogia, Rajive Kumar
BACKGROUND & OBJECTIVES: Mutation of nucleophosmin (NPM1) gene in the absence of FLT3-ITD (FMS related tyrosine kinase 3 - internal tandem duplications) mutation carries a good prognosis in cytogenetically normal acute myeloid leukaemia (AML). NPM1, a multifunctional nucleolar phosphoprotein that shuttles between nucleus and cytoplasm, gets trapped in the cytoplasm when mutated. Immunohistochemical (IHC) demonstration of its aberrant cytoplasmic location (NPMc+) has been suggested as a simple substitute for the standard screening molecular method...
June 2016: Indian Journal of Medical Research
Surender Kumar Sharawat, Vinod Raina, Lalit Kumar, Atul Sharma, Radhika Bakhshi, Sreenivas Vishnubhatla, Ritu Gupta, Sameer Bakhshi
BACKGROUND & OBJECTIVES: Mutations in fms-like tyrosine kinase 3 (FLT3) receptor have significant role in assessing outcome in patients with acute myeloid leukaemia (AML). Data for FLT3 surface expression in relation to FLT3 internal tandem duplication (ITD) status and outcome are not available from India. The objective of the current study was to investigate adult patients with AML for FLT3 expression and FLT3 ITD mutation, and their association with long-term outcome. METHODS: Total 51 consecutive de novo AML patients aged 18-60 yr were enrolled in the study...
May 2016: Indian Journal of Medical Research
Na Gao, Wen-Zheng Yu, Nong-Jian Guo, Xue-Xia Wang, Jian-Rong Sun
Galectin-3 plays an increasingly important role in development and progression of tumor. However, little is known about the clinical impact of galectin-3 in non-acute promyelocytic leukemia (non-M3 AML). Peripheral blood of 298 patients with primary non-M3 AML and 30 normal donors was collected for measurement of galectin-3. Galectin-3 levels were significantly higher compared with the control group (p < .001). Patients with higher galectin-3 levels had lower CR rates (p = .001) and 1-year overall survival (OS) rates (p = ...
October 13, 2016: Leukemia & Lymphoma
Stephen S Y Lam, Eric S K Ho, Bai-Liang He, Wui-Wing Wong, Chae-Yin Cher, Nelson K L Ng, Cheuk-Him Man, Harinder Gill, Alice M S Cheung, Ho-Wan Ip, Chi-Chiu So, Jerome Tamburini, Chi Wai Eric So, Dona N Ho, Chun-Hang Au, Tsun-Leung Chan, Edmond S K Ma, Raymond Liang, Yok-Lam Kwong, Anskar Y H Leung
An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models...
October 5, 2016: Science Translational Medicine
Philipp G Hemmati, Lam G Vuong, Theis H Terwey, Christian F Jehn, Philipp le Coutre, Olaf Penack, Il-Kang Na, Bernd Dörken, Renate Arnold
OBJECTIVES: The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). METHODS: We retrospectively analyzed 274 patients transplanted at our center between 2004 and 2014. RESULTS: The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT (overall p=0...
October 5, 2016: European Journal of Haematology
S Struski, S Lagarde, P Bories, C Puiseux, N Prade, W Cuccuini, M-P Pages, A Bidet, C Gervais, M Lafage-Pochitaloff, C Roche-Lestienne, C Barin, D Penther, N Nadal, I Radford-Weiss, M-A Collonge-Rame, B Gaillard, F Mugneret, C Lefebvre, A Petit, G Leverger, C Broccardo, I Luquet, M Pasquet, E Delabesse
Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, since the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3...
October 3, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Zhuojun Zheng, Xiaodong Li, Yuandong Zhu, Weiying Gu, Xiaobao Xie, Jingting Jiang
This study was designed to perform an acceptable prognostic nomogram for acute myeloid leukemia. The clinical data from 311 patients from our institution and 165 patients generated with Cancer Genome Atlas Research Network were reviewed. A prognostic nomogram was designed according to the Cox's proportional hazard model to predict overall survival (OS). To compare the capacity of the nomogram with that of the current prognostic system, the concordance index (C-index) was used to validate the accuracy as well as the calibration curve...
September 26, 2016: Oncotarget
Elie Traer, Jacqueline Martinez, Nathalie Javidi-Sharifi, Anupriya Agarwal, Jennifer Dunlap, Isabel English, Tibor Kovacsovics, Jeffrey W Tyner, Melissa Wong, Brian J Druker
Potent FLT3 inhibitors such as quizartinib (AC220) have shown promise in treating acute myeloid leukemia (AML) containing FLT3 internal tandem duplication (ITD) mutations. However, responses are not durable and resistance develops within months. In this study, we outline a two-step model of resistance whereby extrinsic microenvironmental proteins FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) protect FLT3-ITD+ MOLM14 cells from AC220, providing time for subsequent accumulation of ligand-independent resistance mechanisms...
September 26, 2016: Cancer Research
Xiaoyu An, Jinping Liu, Na Wang, Di Wang, Liang Huang, Likun Zhang, Jie Cai, Jean-Pierre Wery, Demin Zhou, Jianfeng Zhou, Qi-Xiang Li
Engrafting a M5-AML patient bone marrow (BM) cells into immunocompromised mice (AM7577) achieved serially transferrable stable AML and eventual mortality. The disease starts at BM followed by expansion to peripherals, typical of M5 leukemogenesis, where high leukemic burden in blood is coincident with symptoms/mortality. The leukemic cells in mice have similar myeloid morphology, phenotypes and genotypes (including FLT3-ITD) as the original patient. Autocrine mechanisms of human GM-CSF/IL-3 likely support AM7577 growth in mice...
September 23, 2016: Experimental Hematology
Ioannis Panagopoulos, Synne Torkildsen, Ludmila Gorunova, Aina Ulvmoen, Anne Tierens, Bernward Zeller, Sverre Heim
Fluorescence in situ hybridization examination of a pediatric AML patient whose bone marrow cells carried trisomy 4 and FLT3-ITD mutation, demonstrated that part of the RUNX1 probe had unexpectedly moved to chromosome band 6q25 indicating a cryptic t(6;21)(q25;q22) translocation. RNA sequencing showed fusion of exon 7 of RUNX1 with an intergenic sequence of 6q25 close to the MIR1202 locus, something that was verified by RT-PCR together with Sanger sequencing. The RUNX1 fusion transcript encodes a truncated protein containing the Runt homology domain responsible for both heterodimerization with CBFB and DNA binding, but lacking the proline-, serine-, and threonine-rich (PST) region which is the transcription activation domain at the C terminal end...
September 22, 2016: Oncology Reports
Ashok Kumar Jayavelu, Jennifer N Moloney, Frank-D Böhmer, Thomas G Cotter
In different types of myeloid leukemia, increased formation of reactive oxygen species (ROS) has been noted and associated with aspects of cell transformation, including the promotion of leukemic cell proliferation and migration, as well as DNA damage and accumulation of mutations. Work reviewed in this article has revealed the involvement of NADPH oxidase (NOX)-derived ROS downstream of oncogenic protein-tyrosine kinases in both processes, and the related pathways have been partially identified. FMS-like tyrosine kinase 3 with internal tandem duplications (FLT3-ITD), an important oncoprotein in a subset of acute myeloid leukemias, causes activation of AKT and, subsequently, stabilization of p22(phox), a regulatory subunit for NOX1-4...
September 22, 2016: Experimental Hematology
F Xing, Y N Lin, Q Sun, L Qin, Y J Jia, D L Zhang, K Ru
Objective: To characterize the molecular profile in patients with Ph negative myeloproliferative neoplasms (MPN) by exploring 49 gene mutations. Methods: Targeted gene sequencing were performed to analyze 49 MPN-associated genes in 51 patients with Ph negative MPN, of which CARL (exon 9), NPM1 (exon 12) and CEBPA (TAD, BZIP domains) were investigated by using Sanger sequencing simultaneously, while FLT3-ITD was assessed by PCR method. Results: Mutations were detected in 73.5% (36/49) of genes, and the mutational rates of JAK2-V617F, CALR (exon 9) and MPL were 60...
September 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Jennifer L Poitras, Diane Heiser, Li Li, Bao Nguyen, Kozo Nagai, Amy S Duffield, Christopher Gamper, Donald Small
Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3/ITD) are among the most common mutations in Acute Myeloid Leukemia (AML). Resulting in constitutive activation of the kinase, FLT3/ITD portends a particularly poor prognosis, with reduced overall survival and increased rates of relapse. We previously generated a knock-in mouse, harboring an internal tandem duplication at the endogenous Flt3 locus, which develops a fatal myeloproliferative neoplasm (MPN), but fails to develop acute leukemia, suggesting additional mutations are necessary for transformation...
September 12, 2016: Oncotarget
Tobias Herold, Klaus H Metzeler, Sebastian Vosberg, Luise Hartmann, Vindi Jurinovic, Sabrina Opatz, Nikola P Konstandin, Stephanie Schneider, Evelyn Zellmeier, Bianka Ksienzyk, Alexander Graf, Stefan Krebs, Helmut Blum, Maria Cristina Sauerland, Thomas Büchner, Wolfgang E Berdel, Bernhard J Wörmann, Ulrich Mansmann, Wolfgang Hiddemann, Stefan K Bohlander, Karsten Spiekermann, Philipp A Greif
Deletions of the long arm of chromosome 9 [del(9q)] are a rare but recurring aberration in acute myeloid leukemia (AML). Del(9q) can be found as the sole abnormality or in combination with other cytogenetic aberrations such as t(8;21) and t(15;17). TLE1 and TLE4 were identified to be critical genes contained in the 9q region. We performed whole exome sequencing of 5 patients with del(9q) as the sole abnormality followed by targeted amplicon sequencing of 137 genes of 26 patients with del(9q) as sole or combined with other aberrations...
September 16, 2016: Genes, Chromosomes & Cancer
Yanjun Sun, Hongjie Shen, Ting Xu, Zhen Yang, Huiying Qiu, Aining Sun, Suning Chen, Depei Wu, Yang Xu
DNMT3A mutations are frequent in cytogenetically normal acute myeloid leukemia (CN-AML) patients and can be present many years before the disease develops. However, the clinical significance of DNMT3A mutation burden in CN-AML remains unclear. In this study, 81 DNMT3A mutated adult CN-AML patients in their first complete remission (CR) were enrolled at our center from March 2005 to May 2015. All patients were identified as having DNMT3A exon 23 mutations, and R882H was the most frequent variant (n=49, 60.49%)...
October 2016: Leukemia Research
Haixia Zhou, Changcheng Zheng, Xiaoyu Zhu, Baolin Tang, Juan Tong, Xuhan Zhang, Lei Zhang, Huilan Liu, Zimin Sun
No clinical studies have investigated the role of decitabine as a part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL in patients in NR status. The aim of this study was to identify the potential benefits of decitabine as a prior therapy before salvaged unrelated UCBT for refractory or relapsed childhood AL. Eight consecutive patients with childhood refractory/relapsed AL were enrolled in our study between 2013 and 2014. All patients were in NR status before the time of transplant and had features associated with poor outcomes, such as CNSL, MDS-AML, high WBC count at diagnosis, and hypodiploid status (FLT3+/ITD+)...
September 12, 2016: Pediatric Transplantation
Shinya Osone, Toshihiko Imamura, Takuyo Kanayama, Yusuke Tsuma, Sachiko Kawashima-Goto, Takuya Nakatani, Atsuya Sugimoto, Akari Takai, Mitsuru Miyachi, Shinichi Tamura, Hiroyuki Ishida, Hajime Hosoi
Sorafenib is a promising agent for treating pediatric refractory acute myeloid leukemia (AML) exhibiting FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD); however, its optimal use needs to be established. We report 2 cases of refractory pediatric FLT3-ITD-positive AML treated with sorafenib. Case 1 underwent stem cell transplantation (SCT) without entering remission, despite the use of chemotherapy. This patient relapsed despite receiving post-SCT sorafenib. Chemotherapy combined with sorafenib successfully achieved complete remission in case 2...
August 26, 2016: Journal of Pediatric Hematology/oncology
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