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Genetics on leukemia

Abdelrahman H Elsayed, Xueyuan Cao, Kristine R Crews, Varsha Gandhi, William Plunkett, Jeffrey E Rubnitz, Raul C Ribeiro, Stanley B Pounds, Jatinder K Lamba
AIM: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP. METHOD:  We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68)...
August 8, 2018: Pharmacogenomics
Daisuke Hidaka, Masahiro Onozawa, Junichi Hashiguchi, Naohiro Miyashita, Kohei Kasahara, Shinichi Fujisawa, Eiko Hayase, Kohei Okada, Souichi Shiratori, Hideki Goto, Junichi Sugita, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Tomoyuki Endo, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Kiyotoshi Imai, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Chikara Shimizu, Takeshi Kondo, Takanori Teshima
BACKGROUND: The prognostic effect of Wilms tumor 1 (WT1) expression at the diagnosis of acute myelogenous leukemia (AML) has been controversial. The aim of the present study was to determine the correlations of WT1 expression at the diagnosis of AML with established prognostic alterations. PATIENTS AND METHODS: We analyzed diagnostic bone marrow samples from 252 patients. WT1 expression, single nucleotide polymorphism (SNP) in the WT1 gene (rs16754), and Fms-like tyrosine kinase receptor-3 internal tandem duplication (FLT3-ITD) mutation were analyzed for all patients...
July 17, 2018: Clinical Lymphoma, Myeloma & Leukemia
Takaomi Sanda
Super-enhancers comprise of clusters of enhancers that are typically defined by the ChIP-seq analysis for active histone marks. Although the biological significance of super-enhancers is still controversial, this concept is gaining prominence as useful characteristics of genes that play crucial roles in normal development and pathogenesis of cancer. In various cancer cells, super-enhancers are often associated with genes involved in carcinogenesis. For example, in T-cell acute lymphoblastic leukemia, the oncogenic transcription factor TAL1 and its regulatory partners (GATA3, RUNX1 and MYB) are regulated by super-enhancers; these genes are sensitive to transcriptional inhibition, for example, via the pharmacological approach using a small-molecule CDK7 inhibitor...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Julia Bluhm, Elisa Kieback, Stephen F Marino, Felix Oden, Jörg Westermann, Markus Chmielewski, Hinrich Abken, Wolfgang Uckert, Uta E Höpken, Armin Rehm
Autologous T cells genetically modified with a chimeric antigen receptor (CAR) redirected at CD19 have potent activity in the treatment of B cell leukemia and B cell non-Hodgkin's lymphoma (B-NHL). Immunotherapies to treat multiple myeloma (MM) targeted the B cell maturation antigen (BCMA), which is expressed in most cases of MM. We developed a humanized CAR with specificity for BCMA based on our previously generated anti-BCMA monoclonal antibody. The targeting single-chain variable fragment (scFv) domain exhibited a binding affinity in the low nanomolar range, conferring T cells with high functional avidity...
August 1, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Lane H Miller, Cheng-Kui Qu, Melinda Pauly
The relationship between the hematopoietic stem cell (HSC) population and its surrounding bone marrow microenvironment is a rapidly evolving area of research. Normal HSC processes rely heavily on a complex communication network involving various marrow niches. While leukemogenesis largely results from abnormal genetic activity within the leukemia stem cell itself, mounting evidence indicates a significant contributory role played by marrow niche dysregulation. Furthermore, numerous instances of activating or inactivating germline mutations within marrow microenvironment cells have been shown to be sufficient for development of myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML), even in the context of wild type HSCs...
August 1, 2018: Experimental Hematology
Sharon A Savage, Michael F Walsh
Fanconi anemia (FA) is a DNA repair disorder associated with a high risk of cancer and bone marrow failure. Patients with FA may present with certain dysmorphic features, such as radial ray abnormalities, short stature, typical facies, bone marrow failure, or certain solid malignancies. Some patients may be recognized due to exquisite sensitivity after exposure to cancer therapy. FA is diagnosed by increased chromosomal breakage after exposure to clastogenic agents. It follows autosomal recessive and X-linked inheritance depending on the underlying genomic alterations...
August 2018: Hematology/oncology Clinics of North America
Siddharth Gautam, Niranjan Mishra, Semmannan Kalaiyarasu, Sandeep Kumar Jhade, Richa Sood
Bovine leukemia virus (BLV) causes enzootic leucosis in cattle and is prevalent worldwide. Although recent studies have shown that BLV strains can be classified into 10 distinct genotypes, no information is available regarding the BLV genotype prevalent in cattle in India. To determine the genetic variability of BLV, in this study, 118 adult dairy cows from three states of India were screened for BLV infection by env gp51 specific ELISA and nested PCR. Of the 33 cows found positive by both PCR and ELISA, ten selected BLV strains were subjected to molecular characterization...
July 25, 2018: Transboundary and Emerging Diseases
Cuiping Zhang, Angelo D'Alessandro, Ashley M Wellendorf, Fatima Mohmoud, Juana Serrano-Lopez, John P Perentesis, Kakajan Komurov, Gabriela Alexe, Kimberly Stegmaier, Jeffrey A Whitsett, H Leighton Grimes, Jose A Cancelas
High-risk B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge despite advances in the use of tyrosine kinase inhibitors and chimeric-antigen-receptor engineered T cells. Lymphoblastic-leukemia precursors are highly sensitive to oxidative stress. KLF5 is a member of the Krüppel-like family of transcription factors. KLF5 expression is repressed in B-ALL, including BCR-ABL1+ B-ALL. Here, we demonstrate that forced expression of KLF5 in B-ALL cells bypasses the imatinib resistance which is not associated with mutations of BCR-ABL...
July 3, 2018: Oncotarget
Brandon L Pierce, Peter Kraft, Chenan Zhang
Purpose of review: In this paper, we summarize prior studies that have used Mendelian Randomization (MR) methods to study the effects of exposures, lifestyle factors, physical traits, and/or biomarkers on cancer risk in humans. Many such risk factors have been associated with cancer risk in observational studies, and the MR approach can be used to provide evidence as to whether these associations represent causal relationships. MR methods require a risk factor of interest to have known genetic determinants that can be used as proxies for the risk factor (i...
June 2018: Current Epidemiology Reports
Alveena Zehra, Sitwat Zehra, Muhammad Ismail, Abid Azhar
Objective: Biotransformation of xenobiotics are critical for their metabolism and removal from the body which is carried out by xenobiotic metabolizing enzymes. Individuals carrying variants of genes that encode these enzymes have an altered ability to metabolize xenobiotics which may lead to an increased risk of acute lymphoblastic leukemia. The current study aimed to investigate the impact of GSTM1 and GSTT1 gene deletions in causing predisposition to adult ALL. Methods: The current case-control study involved 62 adult ALL patients and 62 age and gender matched healthy controls...
May 2018: Pakistan Journal of Medical Sciences Quarterly
Amir Farmanbar, Sanaz Firouzi, Wojciech Makałowski, Robert Kneller, Masako Iwanaga, Atae Utsunomiya, Kenta Nakai, Toshiki Watanabe
The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients...
July 19, 2018: Neoplasia: An International Journal for Oncology Research
Aliasghar Keramatinia, Alireza Ahadi, Mohammad Esmaeil Akbari, Maryam Mohseny, Alireza Mosavi Jarahi, Ayad Bahadori-Monfared, Mehrdad Hashemi, Afshin Moradi, Narjes Mehrvar, Elham Kazemi, Abolfazl Movafagh
Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22) (q34;q11.2) encoding for the BCR-ABL fusion oncogene. Growing body of evidence suggests that epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukemic clone escape and disease propagation. The significant of therapeutic role in chronic myeloid leukemia (CML) depends on both genetic and epigenetic mechanisms.  This article focused on the CML and epigenetic and clinical significance...
June 30, 2018: Cellular and Molecular Biology
Isaac Makundi, Yushi Koshida, Yasuyuki Endo, Kazuo Nishigaki
Felis catus gammaherpesvirus 1 (FcaGHV1) is a widely endemic infection of domestic cats. Current epidemiological data identify domestic cats as the sole natural host for FcaGHV1. The Tsushima leopard cat (TLC; Prionailurus bengalensis euptilurus) is a critically endangered species that lives only on Tsushima Island, Nagasaki, Japan. Nested PCR was used to test the blood or spleen of 89 TLCs for FcaGHV1 DNA; three (3.37%; 95% CI, 0.70⁻9.54) were positive. For TLC management purposes, we also screened domestic cats and the virus was detected in 13...
July 19, 2018: Viruses
Laura Cicconi, Pierre Fenaux, Hagop Kantarjian, Martin Tallman, Miguel A Sanz, Francesco Lo-Coco
Acute promyelocytic leukemia (APL) is a subtype of acute leukemia characterized by a unique t(15;17) translocation generating the PML/RARA fusion gene and hybrid oncoprotein. Besides its critical role in leukemogenesis, this genetic aberration serves as a disease-specific biomarker for rapid diagnosis and monitoring of minimal residual disease (MRD). Moreover, PML/RARA is specifically targeted by All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two agents that synergistically act to induce degradation of the oncoprotein...
July 19, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Pingli Yao, Xia He, Rong Zhang, Rongsheng Tong, Hongtao Xiao
OBJECTIVES: The effect of methotrexate (MTX)-related adverse reaction on hematologic neoplasms patients is controversial. We performed this meta-analysis to assess the association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphism and the adverse reaction after MTX using. METHODS: We searched for qualified studies according to PubMed, the Cochrane Library, and the Web of Science. The meta-analysis was performed by Review Manager 5.3. The analysis was conducted to compare risk ratios (RRs) with the corresponding 95% confidence interval (95% CI) to evaluate the relationship between different toxicity reactions and the genotype of MTHFR...
July 19, 2018: Hematology (Amsterdam, Netherlands)
Kristen M Wilding, J Porter Hunt, Joshua W Wilkerson, Parker J Funk, Rebecca L Swensen, William C Carver, M Lance Christian, Bradley C Bundy
Approximately one third of protein therapeutics are produced in E. coli, targeting a wide variety of diseases. However, due to immune recognition of endotoxin (a lipid component in the E. coli cell membrane), these protein products must be extensively purified before application to avoid adverse reactions such as septic shock. E. coli-based cell-free protein synthesis (CFPS), which has emerged as a promising platform for the development and production of enhanced protein therapeutics, provides a unique opportunity to remove endotoxins prior to protein expression due to its open environment and the absence of live cells...
July 19, 2018: Biotechnology Journal
Guoqiao Zheng, Hongyao Yu, Anna Kanerva, Asta Försti, Kristina Sundquist, Kari Hemminki
BACKGROUND: Borderline ovarian tumors (BOTs) are a subgroup of ovarian malignancies with low malignant potential. Very limited earlier data are available on familial clustering of BOTs with other cancers. We aim to explore histology-specific familial associations among BOTs and associations between BOT and any invasive cancers. METHODS: Based on 16.1 million individuals in the Swedish Family-Cancer Database, we estimated familial risks for overall or histology-specific BOT patients considering both BOT and any invasive cancers in first-degree relatives (parents or siblings), as well as familial risks for invasive cancers considering family history of BOTs...
July 17, 2018: Cancer Epidemiology, Biomarkers & Prevention
Takashi Kurata, Kazuyuki Matsuda, Koichi Hirabayashi, Tomonari Shigemura, Kazuo Sakashita, Tatsutoshi Nakahata, Kenichi Koike
BACKGROUND: Encouraging responses to histone deacetylase inhibitors have been reported for hematologic malignancies. Here, we report effects of panobinostat and 5-azacytidine on the proliferation of juvenile myelomonocytic leukemia (JMML) CD34+ cells. PROCEDURE: We previously reported that stimulation of JMML CD34+ cells with stem cell factor and thrombopoietin on irradiated murine AGM-S3 cells led to substantial expansion of JMML CD34+ cells that contained leukemic stem cells capable of transplantation into immunodeficient mice...
July 16, 2018: Pediatric Blood & Cancer
Viviane Lamim Lovatel, Daiane Corrêa de Souza, Tatiana Fonseca Alvarenga, Roberto R Capela de Matos, Claudia Diniz, Marcia Trindade Schramm, Juan Clinton Llerena Júnior, Maria Luiza Macedo Silva, Eliana Abdelhay, Teresa de Souza Fernandez
Background: Myelodysplastic syndrome (MDS) is rare in the pediatric age group and it may be associated with inheritable bone marrow failure (BMF) such as Fanconi anemia (FA). FA is a rare multi-system genetic disorder, characterized by congenital malformations and progressive BMF. Patients with FA usually present chromosomal aberrations when evolving to MDS or acute myeloid leukemia (AML). Thus, the cytogenetic studies in the bone marrow (BM) of these patients have an important role in the therapeutic decision, mainly in the indication for hematopoietic stem cell transplantation (HSCT)...
2018: Molecular Cytogenetics
Carla de Castro Sant' Anna, Alberto Gomes Ferreira Junior, Paulo Soares, Fabricio Tuji, Eric Paschoal, Luiz Cláudio Chaves, Rommel Rodriguez Burbano
Cancer is a genetic disease characterized by uncontrolled cell growth and metastasis. Cancer can have a number of causes, such the activation of oncogenes, the inactivation of tumor-suppressing genes, mutagenesis provoked by external factors, and epigenetic modifications. The development of diagnostic tools and treatments using a molecular biological approach permits the use of sensitive, low-cost, noninvasive tests for cancer patients. Biomarkers can be used to provide rapid, personalized oncology, in particular the molecular diagnosis of chronic myeloid leukemia, and gastric, colon, and breast cancers...
July 13, 2018: Clinical and Experimental Medicine
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