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Myeloid leukemia

Elizabeth E Hjort, Weiqi Huang, Liping Hu, Elizabeth A Eklund
Icsbp/Irf8 is an interferon regulatory transcription factor that functions as a suppressor of myeloid leukemias. Consistent with this activity, Icsbp represses a set of genes encoding proteins that promote cell proliferation/survival. One such gene encodes Gas2, a calpain inhibitor. We previously found that increased Gas2-expression in Bcr-abl+ cells stabilized βcatenin; a Calpain substrate. This was of interest, because βcatenin contributes to disease progression in chronic myeloid leukemia (CML). Calpain has additional substrates implicated in leukemogenesis, including Stat5...
October 19, 2016: Oncotarget
Allison B Norvil, Christopher J Petell, Lama Abdullah Alabdi, Lanchen Wu, Sandra Rossie, Humaira Gowher
The catalytic domains of the de novo DNA methyltransferases, Dnmt3a-C and Dnmt3b-C are highly homologous. However their unique biochemical properties could potentially contribute to differences in the substrate preferences or biological functions of these enzymes. Dnmt3a-C forms tetramers through interactions at the dimer interface, which also promote multimerization on DNA and cooperativity. Similar to processive enzymes, cooperativity allows Dnmt3a-C to methylate multiple sites on the same DNA molecule, however it is unclear whether Dnmt3b-C methylates DNA by cooperative or processive mechanism...
October 21, 2016: Biochemistry
Neelam N Redkar, Udit Saraf, Rajit Pillai, Kavita J RawatAssociate Professor In General Medicine Seth G S Medical College And K E M H Mumbai Maharashtra
No abstract text is available yet for this article.
October 2016: Journal of the Association of Physicians of India
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
Kran Suknuntha, Thanyatip Thita, Padma Priya Togarrati, Piyanee Ratanachamnong, Patompon Wongtrakoongate, Sirada Srihirun, Igor Slukvin, Suradej Hongeng
Wnt signaling pathway plays a major role in leukemogenesis of myeloid leukemia. Aberrancy in its regulation results in hyperactivity of the pathway contributing to leukemia propagation and maintenance. To investigate effects of Wnt pathway inhibition in leukemia, we used human leukemia cell lines (i.e., K562, HL60, THP1, and Jurkat) and several Wnt inhibitors, including XAV939, IWP2 and FH535. Our results showed that leukemia cell lines (>95 % cells) had increased endogenous levels of β-catenin as compared to mononuclear cells from healthy donors (0 %)...
October 20, 2016: International Journal of Hematology
Emmanuelle Ginoux, Diane Kottler, Bruno Anglaret, Brigitte Balme, Claude-Eric Bulabois, François Skowron
No abstract text is available yet for this article.
September 2016: JAAD Case Reports
Rui Su, Jia-Nan Gong, Ming-Tai Chen, Li Song, Chao Shen, Xin-Hua Zhang, Xiao-Lin Yin, Hong-Mei Ning, Bing Liu, Fang Wang, Yan-Ni Ma, Hua-Lu Zhao, Jia Yu, Jun-Wu Zhang
Aberrant activation of c-Myc plays an important oncogenic role via regulating a series of coding and non-coding genes in acute myeloid leukemia (AML). Histone deacetylases (HDACs) can remove acetyl group from histone and regulate gene expression via changing chromatin structure. Here, we found miR-451 is abnormally down-regulated in AML patient samples; c-Myc recruits HDAC3 to form a transcriptional suppressor complex, co-localizes on the miR-451 promoter, epigenetically inhibits its transcription and finally induces its downregulation in AML...
October 15, 2016: Oncotarget
Qie He, Junfeng Zhu, David Dingli, Jasmine Foo, Kevin Zox Leder
Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib) have been developed to treat Chronic Myeloid Leukemia (CML). Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies...
October 2016: PLoS Computational Biology
Paul B Koller, Hagop M Kantarjian, Graciela M Nogueras-Gonzalez, Elias Jabbour, Srdan Verstovsek, Gautam Borthakur, Zeev Estrov, William G Wierda, Guillermo Garcia-Manero, Alessandra Ferrajoli, Farhad Ravandi, Susan M O'Brien, Jorge E Cortes
BACKGROUND: Some patients with chronic myeloid leukemia (CML) have a history of previous malignancies. To the authors' knowledge, outcomes for CML diagnosed in these patients have not been well described. The current study was conducted to determine the outcome of patients with CML and a history of prior malignancies. METHODS: The current study included patients who were enrolled in clinical trials of tyrosine kinase inhibitors as initial therapy for CML in chronic phase from July 2000 to January 2014...
October 20, 2016: Cancer
Lucia Pavlikova, Mario Seres, Denisa Imrichova, Milan Hano, Andrej Rusnak, Martina Zamorova, Jaroslav Katrlik, Albert Breier, Zdena Sulova
In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/VCR) by selection with vincristine (VCR) and lenalidomide (LEN)...
October 2016: General Physiology and Biophysics
Antonella Caivano, Francesco La Rocca, Vittorio Simeon, Marco Girasole, Simone Dinarelli, Ilaria Laurenzana, Angelo De Stradis, Luciana De Luca, Stefania Trino, Antonio Traficante, Giovanni D'Arena, Giovanna Mansueto, Oreste Villani, Giuseppe Pietrantuono, Luca Laurenti, Luigi Del Vecchio, Pellegrino Musto
PURPOSE: The use of extracellular vesicles (EVs) from body fluids as "liquid biopsies" is emerging as a promising approach for the diagnosis, prognosis and therapeutic monitoring of cancer patients. MicroRNA-155 (miR155), a non-coding transcript of the B-cell integration cluster (BIC) gene, has been reported to play a critical role in the pathogenesis of several types of hematologic malignancies (HMs) in which high miR155 levels have been found. At yet, however, the EV miR155 level and its putative clinical relevance in sera of HM patients have not been reported...
October 19, 2016: Cellular Oncology (Dordrecht)
Annette Romanski, Gesine Bug
Histone deacetylase (HDAC) inhibitors are promising drugs. These agents lead to growth inhibition, cell cycle arrest, premature senescence, and apoptosis of malignant cells. Aim of our studies was to determine the efficacy of HDAC inhibitors on the clinically most relevant population of human leukemic progenitor cells in vitro. We here present stroma-free long-term cultures (LTC) of primary acute myeloid leukemia (AML) cells as a useful system for drug sensitivity testing in functional assays. AML-LTC are established by isolating mononuclear cells from peripheral blood samples of AML patients followed by selection of CD34(+) progenitor cells...
2017: Methods in Molecular Biology
Fabian Treude, Tobias Gladbach, Jacqueline Plaster, Jörg Hartkamp
Aberrant histone deacetylase (HDAC) activity often correlates with neoplastic transformation and inhibition of HDACs by small molecules has emerged as a promising strategy to treat hematological malignancies in particular. Treatment with HDAC inhibitors (HDACis) often prompts tumor cells to undergo apoptosis, thereby causing a caspase-dependent cleavage of target proteins. An unexpectedly large number of proteins are in vivo caspase substrates and defining caspase-mediated substrate specificity is a major challenge...
2017: Methods in Molecular Biology
Yoshitaka Sunami, Akihiko Gotoh, Naoki Watanabe, Yoko Edahiro, Yasuharu Hamano, Hironori Harada, Norio Komatsu
Pleural effusion may occur as a rare complication associated with myeloid hematological malignancies. However, it occasionally occurs in patients with myelodysplastic/myeloproliferative neoplasms(MDS/MPN), especially in chronic myelomonocytic leukemia(CMML)with marked leukocytosis. Pleural effusion can also develop in hematological disorders with bone marrow fibrosis. Here, we report a case of CMML with bone marrow fibrosis, in which massive pleural effusion developed rapidly during cytoreductive therapy with hydroxycarbamide(HU)...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Kate Stringaris, David Marin, A John Barrett, Robert Hills, Catherine Sobieski, Kai Cao, Jerome G Saltarrelli, May Daher, Hila Shaim, Nathaniel Smith, David Linch, Rosemary Gale, Christopher Allen, Takuya Sekine, Rohtesh Mehta, Richard Champlin, Elizabeth J Shpall, Hagop Kantarjian, Guillermo Garcia-Manero, Katayoun Rezvani
Myelodysplastic syndromes (MDS) are a group of hematopoietic disorders affecting the myeloid lineage, characterized by cytopenias and clonal evolution to acute myeloid leukemia (AML). We hypothesized that natural killer (NK) cells and their activating killer immunoglobulin-like receptors (aKIRs) influence the immune surveillance and clinical outcome of patients with MDS. Here, we first examined the distribution of aKIR genes and haplotype in two independent cohorts of MDS and AML patients. The median number of aKIR genes was lower in MDS patients than healthy controls (2 vs...
October 19, 2016: Blood
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
Konstantinos Tzelepis, Hiroko Koike-Yusa, Etienne De Braekeleer, Yilong Li, Emmanouil Metzakopian, Oliver M Dovey, Annalisa Mupo, Vera Grinkevich, Meng Li, Milena Mazan, Malgorzata Gozdecka, Shuhei Ohnishi, Jonathan Cooper, Miten Patel, Thomas McKerrell, Bin Chen, Ana Filipa Domingues, Paolo Gallipoli, Sarah Teichmann, Hannes Ponstingl, Ultan McDermott, Julio Saez-Rodriguez, Brian J P Huntly, Francesco Iorio, Cristina Pina, George S Vassiliou, Kosuke Yusa
Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates...
October 18, 2016: Cell Reports
András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Ana Leticia Maragno, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Gemma L Kelly, Jia-Nan Gong, Donia M Moujalled, Alain Bruno, Márton Csekei, Attila Paczal, Zoltán B Szabo, Szabolcs Sipos, Gábor Radics, Agnes Proszenyak, Balázs Balint, Levente Ondi, Gábor Blasko, Alan Robertson, Allan Surgenor, Pawel Dokurno, Ijen Chen, Natalia Matassova, Julia Smith, Christopher Pedder, Christopher Graham, Aurélie Studeny, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Gravé, David Segal, Chris D Riffkin, Giovanna Pomilio, Laura C A Galbraith, Brandon J Aubrey, Margs S Brennan, Marco J Herold, Catherine Chang, Ghislaine Guasconi, Nicolas Cauquil, Fabien Melchiore, Nolwen Guigal-Stephan, Brian Lockhart, Frédéric Colland, John A Hickman, Andrew W Roberts, David C S Huang, Andrew H Wei, Andreas Strasser, Guillaume Lessene, Olivier Geneste
Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway...
October 19, 2016: Nature
Sergio Pina-Oviedo, Carlos A Torres-Cabala, Roberto N Miranda, Michael T Tetzlaff, Selina Singh, Ronald P Rapini, Victor G Prieto, Phyu P Aung
Leukemia cutis develops in <4% of all acute leukemias. Concurrent acute myeloid leukemia (AML) and Langerhans cell histiocytosis (LCH) is rare, with most cases involving lymph nodes or spleen, and no cutaneous involvement. We report the case of a 59-year-old man who presented with fever, malaise, and fatigue. The CBC showed leukocytosis (30.4 × 10/L, 9% blasts), anemia, and thrombocytopenia. Bone marrow biopsy was diagnosed with AML, not otherwise specified, with mutations of FLT3 and IDH2 (R140Q). The patient developed skin rash on the right flank with the clinical differential diagnosis of herpes simplex virus or varicella-zoster virus infection/reactivation versus leukemia cutis...
October 18, 2016: American Journal of Dermatopathology
Delphine Ohayon, Alessia De Chiara, Nicolas Chapuis, Céline Candalh, Julie Mocek, Jean-Antoine Ribeil, Lamya Haddaoui, Norbert Ifrah, Olivier Hermine, Frédéric Bouillaud, Philippe Frachet, Didier Bouscary, Véronique Witko-Sarsat
Cytosolic proliferating cell nuclear antigen (PCNA), a scaffolding protein involved in DNA replication, has been described as a key element in survival of mature neutrophil granulocytes, which are non-proliferating cells. Herein, we demonstrated an active export of PCNA involved in cell survival and chemotherapy resistance. Notably, daunorubicin-resistant HL-60 cells (HL-60R) have a prominent cytosolic PCNA localization due to increased nuclear export compared to daunorubicin-sensitive HL-60 cells (HL-60S)...
October 19, 2016: Scientific Reports
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