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Genetics on leukemia

Jonas Samuel Jutzi, Titiksha Basu, Maximilian Pellmann, Sandra Kaiser, Doris Steinemann, Mathijs A Sanders, Adil S A Hinai, Annelieke Zeilemaker, Sarolta Bojtine Kovacs, Christoph Koellerer, Jenny Ostendorp, Konrad Aumann, Wei Wang, Emmanuel Raffoux, Bruno Cassinat, Lars Bullinger, Brigitte Schlegelberger, Peter J M Valk, Heike Luise Pahl
In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in AML patients and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant NFE2 in mice causes a myeloproliferative phenotype...
February 12, 2019: Blood
C Ferri, N Weich, L Gutiérrez, C De Brasi, M R Bengió, P Zapata, A Fundia, I Larripa
The BCR-ABL1 oncogene is associated with chronic myeloid leukemia (CML) pathogenesis, but the molecular mechanisms that initiate leukemogenesis are still unclear. Cancer pathogenesis has been associated with genetic alterations that may lead to inactivation of tumor suppressor genes. Phosphatase and tensin homolog (PTEN) is frequently deleted or inactivated in various tumors. A recently discovered variant of PTEN, PTEN-Long (PTEN-L), results from an alternative translation initiation site located upstream of the canonic AUG and generates a protein of 576 amino acids instead the expected protein of 403 amino acids...
February 7, 2019: Gene
Jaurès Blanc Mettral, Nicolas Faller, Sandra Cruchon, Loïc Sottas, Thierry Buclin, Laurent Schild, Eva Choong, Aimable Nahimana, Laurent A Decosterd
Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Moreover, drug ionization state can be modified by the hypoxic and acidic surrounding extracellular microenvironment. In Philadelphia-positive leukemia, the drug efflux transporter P-glycoprotein has been well demonstrated to modulate the cell disposition of imatinib, a tyrosine kinase inhibitor targeted to intracellular BCR-ABL oncoprotein...
February 7, 2019: Drug Metabolism Letters
Daniel A Arber, Attilio Orazi
The diagnostic criteria for chronic myelomonocytic leukemia were recently revised in the 2016 World Health Organization classification update and include new and revised subtypes. In addition, molecular genetic studies have provided new insights into the prognosis and diagnosis of this myeloid neoplasm. This review summarizes the 2016 changes to the diagnostic criteria, discusses potential future changes that may impact diagnosis and provides an overview of recent advances in the diagnosis and prognosis determination of chronic myelomonocytic leukemia...
February 5, 2019: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Tilmann Bochtler, Georg-Martin Haag, Sarah Schott, Matthias Kloor, Alwin Krämer, Carsten Müller-Tidow
BACKGROUND: Some hematological malignancies arise in persons with a hereditary predisposition. The hereditary nature of these diseases often goes unrecognized, particularly when symptoms begin in adulthood. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed. RESULTS: Many rare germline mutations have been identified that lead to acute leukemia and myelodysplastic syndromes. They differ from one another with respect to their penetrance, the age of onset of disease, and the clinical manifestations...
December 14, 2018: Deutsches Ärzteblatt International
Yan Liu, Xiaofeng Xu, Peng Lin, Yuanming He, Yawen Zhang, Biyin Cao, Zubin Zhang, Gautam Sethi, Jinbao Liu, Xiumin Zhou, Xinliang Mao
Chemoresistance is a leading obstacle in effective management of advanced prostate cancer (PCa). A better understanding of the molecular mechanisms involved in PCa chemoresistance could improve treatment of patients with PCa. In the present study, using immunohistochemical, -chemistry, and -precipitation assays with cells from individuals with benign or malignant prostate cancer or established PCa cell lines, we found that the oncogenic transcription factor pre-B-cell leukemia homeobox-1 (PBX1) promotes PCa cell proliferation and confers to resistance against common anti-cancer drugs such as doxorubicin and cisplatin...
February 4, 2019: Journal of Biological Chemistry
Y Yang, S Chu, S Shang, Z Yang, C Wang
Bovine leukemia virus (BLV) causes enzootic leucosis in cattle and is classified into 10 genotypes with a worldwide distribution, except for several European countries, Australia, and New Zealand. Although BLV is widespread in Chinese cows with the positive rate of 49.1% at the individual level, very little is known about the BLV genotype in dairy cattle in China. To determine BLV genetic variability in cows in China, 112 BLV-positive samples from 5 cities in China were used for BLV molecular characterization in this study...
January 31, 2019: Journal of Dairy Science
Jane E Churpek, Emery H Bresnick
The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations...
February 1, 2019: Journal of Clinical Investigation
Prabakaran Paulraj, Steven Diamond, Faisal Razzaqi, Dan Ozeran, Maria Longhurst, Erica F Andersen, Reha M Toydemir, Bo Hong
The t(7;21)(p22;q22) resulting in RUNX1-USP42 fusion, is a rare but recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prognostic significance of this translocation has not been well established due to the limited number of patients. Herein, we report three pediatric AML patients with t(7;21)(p22;q22). All three patients presented with pancytopenia or leukopenia at diagnosis, accompanied by abnormal immunophenotypic expression of CD7 and CD56 on leukemic blasts...
January 31, 2019: Genes, Chromosomes & Cancer
K I Zarubina, E N Parovichnikova, G A Baskhaeva, A E Krasilnikova, O A Gavrilina, B V Biderman, A B Sudarikov, S N Bondarenko, Y O Davydova, I V Galtseva, A N Sokolov, V V Troitskaya, V G Savchenko
B-cell acute lymphoblastic leukemia (B-ALL) is a diverse group of malignant blood disorders both with regard to the biological properties of the tumor and to therapeutic approaches. Immunophenotyping, molecular genetic techniques, whole-genome sequencing characterize B-ALL as a very diverse group for sensitivity to chemotherapy and prognosis. We present three clinical cases of patients with B-ALL and expected good response to standard therapy, in whom standard protocol treatment failured: refractoriness, persistence of minimal residual disease (MRD), and progression (MRD increase)...
August 17, 2018: Terapevticheskiĭ Arkhiv
Miguel Olivas-Aguirre, Igor Pottosin, Oxana Dobrovinskaya
Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of hematologic malignancies, arising from diverse genetic alterations in the early lymphocyte development. T-cell subtype of ALL (T-ALL) accounts for about 15% and 25% of ALL in children and adults, respectively. Being less frequent among ALL subtypes, T-ALL represents a high-risk factor for poor prognosis due to its aggressiveness and resistance to common antileukemic drugs. Mitochondria were widely explored recently as a target for anticancer treatment because they are involved in a metabolic reprogramming of a cancer cell and play key roles in reactive oxygen species generation, Ca2+ signaling, and cell death induction...
January 30, 2019: Journal of Leukocyte Biology
Dong Hoon Lee, Go Woon Kim, So Hee Kwon
Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL) with genetic alterations of BCL-2, KMT2B, and KMT6. FL is refractory to conventional chemotherapy and is still incurable in most patients. Thus, new drugs and/or novel combination treatment strategies are needed to further improve FL patient outcome. We investigated the efficacy of the histone deacetylase 6 (HDAC6) inhibitor A452 combined with a Bruton's tyrosine kinase (BTK) inhibitor ibrutinib on NHL and the underlying mechanisms compared with the current clinically tested HDAC6 inhibitor ACY-1215...
January 29, 2019: Molecular Carcinogenesis
Shaneice R Mitchell, Karilyn Larkin, Nicole R Grieselhuber, Tzung-Huei Lai, Matthew Cannon, Shelley Orwick, Pratibha Sharma, Yerdanose Asemelash, Pu Zhang, Virginia M Goettl, Larry Beaver, Alice Mims, Vinay K Puduvalli, James S Blachly, Amy Lehman, Bonnie Harrington, Sally Henderson, Justin T Breitbach, Katie E Williams, Shuai Dong, Erkan Baloglu, William Senapedis, Karl Kirschner, Deepa Sampath, Rosa Lapalombella, John C Byrd
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities...
February 12, 2019: Blood Advances
Michael Tveden Gundesen, Thomas Lund, Hanne E H Moeller, Niels Abildgaard
PURPOSE OF REVIEW: We discuss current topics on the definition of plasma cell leukemia and the distinction between plasma cell leukemia and multiple myeloma. Moreover, we review the latest literature on how to treat plasma cell leukemia. RECENT FINDINGS: Plasma cell leukemia is clinically and genetically distinct from multiple myeloma. Plasma cell leukemia is defined by the observation in blood of more than 20% clonal plasma cells by differential count of the leucocytes or by counting more than 2 × 109 per liter circulating clonal plasma cells...
January 28, 2019: Current Oncology Reports
C Chabannon, R Bouabdallah, S Fürst, A Granata, C Saillard, N Vey, D Mokart, E Fougereau, C Lemarie, B Mfarrej, D Blaise, B Calmels
CAR-T cells are genetically modified human lymphocytes and gene therapy medicinal products. They are developed to treat cancers that express a membrane antigen targeted by the CAR. The FDA approved the two first-in-class medicinal products in 2017 and EMA in August 2018; both are autologous CAR-T cells targeting CD19 that is expressed at the surface of normal B-cells throughout their differentiation, and on B-cell lymphoid malignancies. Clinical efficacy was demonstrated for B-cell acute lymphoblastic leukemias, non-Hodgkin's lymphoma and chronic lymphocytic leukemia, although the marketing authorizations are less liberal in terms of indications...
January 24, 2019: La Revue de Médecine Interne
Adalgisa Condoluci, Davide Rossi
Several recurrently deregulated pathways implicated in the development of chronic lymphocytic leukemia (CLL) have been described over the last decades. Knowledge of the CLL genetic heterogeneity led to the definition of molecular biomarkers informing about prognosis and treatment outcome. Areas covered: English literature published from January 2008 through December 2018 was searched in PubMed, Cochrane Central Register of Controlled Trials, and hematology meeting abstracts to obtain literature on clinical predictive factors for CLL...
January 28, 2019: Expert Review of Hematology
Keisuke Kataoka, Hiroaki Miyoshi, Seiji Sakata, Akito Dobashi, Lucile Couronné, Yasunori Kogure, Yasuharu Sato, Kenji Nishida, Yuka Gion, Yuichi Shiraishi, Hiroko Tanaka, Kenichi Chiba, Yosaku Watatani, Nobuyuki Kakiuchi, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Masahiro Onozawa, Takanori Teshima, Yumiko Yoshiki, Tadao Ishida, Kenshi Suzuki, Kazuyuki Shimada, Akihiro Tomita, Motohiro Kato, Yasunori Ota, Koji Izutsu, Ayako Demachi-Okamura, Yoshiki Akatsuka, Satoru Miyano, Tadashi Yoshino, Philippe Gaulard, Olivier Hermine, Kengo Takeuchi, Koichi Ohshima, Seishi Ogawa
Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%)...
January 25, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
M Zmigrodzka, A Rzepecka, M Krzyzowska, O Witkowska-Pilaszewicz, A Cywinska, A Winnicka
The overexpression of cyclooxygenase-2 (COX-2) has been documented in many types of cancer occurring in humans and animals. Increasing evidences have shown that the overexpression of COX-2 and increased production of prostaglandin E2 (PGE2 ) correlate with poor prognosis in human solid tumours and hematological malignancies. Both, in vitro and in vivo studies have demonstrated that increased proliferation of cancer cells as well as an impairment of anti-tumour immunity are influenced by the overexpression of this enzyme...
October 2018: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Amro Elshoury, Amanda Przespolewski, Jeffrey Baron, Eunice S Wang
Mutations of the FLT3 gene are among most common genetic abnormalities occurring in acute myeloid leukemia (AML) and are associated with dismal prognosis. Tremendous effort has been devoted to developing clinically effective FLT3 inhibitors. First generation inhibitors consisted of multi-kinase inhibitors (sorafenib, lestaurtinib, midostaurin), which blocked FLT3 as well as multiple other kinase receptors. The failure of these agents to induce durable responses led to the development of second generation FLT3 tyrosine kinase inhibitors (quizartinib, crenolinib, gilteritinib) exhibiting high potency and specificity for mutant FLT3 kinases and sustained in vivo FLT3 inhibition...
January 25, 2019: Expert Review of Anticancer Therapy
Luisa Schmidt, Elizabeth Heyes, Lisa Scheiblecker, Thomas Eder, Giacomo Volpe, Jon Frampton, Claus Nerlov, Peter Valent, Jolanta Grembecka, Florian Grebien
The gene encoding the transcription factor C/EBPα is mutated in 10-15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. Oncogenic C/EBPα p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex...
January 24, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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