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Leukemia And Mutation And Diagnosis

Esther Onecha, Maria Linares, Inmaculada Rapado, Yanira Ruiz-Heredia, Pilar Martinez-Sanchez, Teresa Cedena, Marta Pratcorona, Jaime Perez Oteyza, Pilar Herrera, Eva Barragan, Pau Montesinos, Jose Antonio Garcia Vela, Elena Magro, Eduardo Anguita, Angela Figuera, Rosalia Riaza, Pilar Martinez-Barranco, Beatriz Sanchez-Vega, Josep Nomdedeu, Miguel Gallardo, Joaquin Martinez-Lopez, Rosa Ayala
A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease (MRD) negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for MRD assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-SNVs. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by NGS, evaluating the level of mutations detected at diagnosis...
August 9, 2018: Haematologica
Vikas Madan, Lin Han, Norimichi Hattori, Weoi Woon Teoh, Anand Mayakonda, Qiao-Yang Sun, Ling-Wen Ding, Hazimah Binte Mohd Nordin, Su Lin Lim, Pavithra Shyamsunder, Pushkar Dakle, Janani Sundaresan, Ngan B Doan, Masashi Sanada, Aiko Sato-Otsubo, Manja Meggendorfer, Henry Yang, Jonathan W Said, Seishi Ogawa, Torsten Haferlach, Der-Cherng Liang, Lee-Yung Shih, Tsuyoshi Nakamaki, Q Tian Wang, H Phillip Koeffler
Chromosomal translocation t(8;21)(q22;q22) which leads to generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in about 10% of acute myelogenous leukemia (AML). To uncover somatic mutations that cooperate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in-depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency...
August 9, 2018: Haematologica
Marielle Perry, Sarah Bertoli, Clément Rocher, Sandrine Hayette, Sophie Ducastelle, Fiorenza Barraco, Hélène Labussière-Wallet, Gilles Salles, Christian Recher, Xavier Thomas, Etienne Paubelle
BACKGROUND: Outcome of patients with mutation of the FLT3 tyrosine kinase domain (FLT3-TKD) in acute myeloid leukemia (AML) remains controversial. PATIENTS AND METHODS: Herein, we present a retrospective study of 126 newly diagnosed patients with AML performed in 2 French centers. RESULTS: FLT3-TKD mutations represented 12.7% of patients, whereas FLT3-internal tandem duplication (ITD) mutation was observed in 20.6% of AML cases and 1.6% of patients harbored both anomalies...
June 13, 2018: Clinical Lymphoma, Myeloma & Leukemia
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
Shiro Ide, Shin Ohara, Morihiro Inoue, Jian Hua, Masao Hagihara
A 77-year-old male with hyperleukocytosis and thrombocytopenia was diagnosed with Philadelphia chromosome (Ph) -negative B-cell acute lymphoblastic leukemia (ALL) ; he was treated with induction chemotherapy. Despite an initial complete remission, hyperleukocytosis was returned 18 months later. A bone marrow smear revealed a substantial increase in the number of myeloid cells with each stage of differentiation, which was markedly different from the initial presentation, resulting in the diagnosis of Ph-negative myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Adam S Nelson, Kasiani C Myers
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome classically associated with exocrine pancreatic dysfunction and neutropenia, with a predisposition toward progressive marrow failure, risk of myelodysplastic syndrome, and leukemia. Most patients carry biallelic mutations in the Shwachman-Bodian-Diamond Syndrome gene, which is an integral component of ribosome maturation and biogenesis. This article reviews the diagnosis, clinical characteristics, and treatment modalities of SDS, and reports advances in the understanding of the molecular pathophysiology of SDS...
August 2018: Hematology/oncology Clinics of North America
Katrin Schranz, Max Hubmann, Egor Harin, Sebastian Vosberg, Tobias Herold, Klaus H Metzeler, Maja Rothenberg-Thurley, Hanna Janke, Kathrin Bräundl, Bianka Ksienzyk, Aarif M N Batcha, Sebastian Schaaf, Stephanie Schneider, Stefan K Bohlander, Dennis Görlich, Wolfgang E Berdel, Bernhard J Wörmann, Jan Braess, Stefan Krebs, Wolfgang Hiddemann, Ulrich Mansmann, Karsten Spiekermann, Philipp A Greif
In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of FLT3 are frequent mutations associated with unfavorable prognosis. At diagnosis, the FLT3- ITD status is routinely assessed by fragment analysis, providing information about the length but not the position and sequence of the ITD. To overcome this limitation, we performed cDNA-based high-throughput amplicon sequencing (HTAS) in 250 FLT3- ITD positive AML patients, treated on German AML Cooperative Group (AMLCG) trials. FLT3- ITD status determined by routine diagnostics was confirmed by HTAS in 242 out of 250 patients (97%)...
July 10, 2018: Oncotarget
Michael W Schmitt, Justin R Pritchard, Scott M Leighow, Bella I Aminov, Lan Beppu, Daniel Seung Kim, John Graeme Hodgson, Victor M Rivera, Lawrence A Loeb, Jerald Radich
PURPOSE: Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e. therapies for which no single target mutation can cause resistance. Since the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes, and prioritize pan-target inhibitors for indications where on-target mutations are most likely...
July 24, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Utkarsh H Acharya, Anna B Halpern, Qian Vicky Wu, Jenna M Voutsinas, Roland B Walter, Seongseok Yun, Mohammed Kanaan, Elihu H Estey
Aim: Acute myeloid leukemia (AML) is an aggressive hematopoietic clonal disorder characterized by the increased blasts and poor survival outcome, which is mainly driven by cytogenetic and molecular abnormalities. Here, we investigated the prognostic impact of other demographic parameters on the survival outcomes in AML patients. Method: We reviewed the Surveillance, Epidemiology, and End Result (SEER) database to collect demographic information, including age, diagnosis, gender, race, and geographic region in patients with non-acute promyelocytic leukemia AML, between 2004-2008...
2018: Journal of Drug Assessment
T Y Wang, Z J Li, R Lyu, M W Fu, W W Sui, W Y Huang, W Liu, G An, S H Deng, L G Qiu
Objective: To investigate the curative effect of hairy cell leukemia by clatabine. Methods: The clinical data of 24 patients with hairy cell leukemia treated by cladribine from November 2006 to October 2017 were analyzed retrospectively, then the curative effect and adverse drug reaction were analyzed. Results: ① A total of 24 patients including 22 male and 2 female, and the median age was 49.5 years (range 33 to 76) at diagnosis. There were 20 patients with of splenomegaly (4 patients with mild splenomegaly, 4 moderate splenomegaly, and 12 massive splenomegaly), 3 patients with enlargement of lymph nodes, and 1 patients who had undergone splenectomy...
June 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
B F Gong, Y H Tan, A J Liao, J Li, Y Y Mao, N Lu, Y Ding, E L Jiang, T J Gong, Z L Jia, Y Sun, B Z Li, S C Liu, J Du, W R Huang, H Wei, J X Wang
Objective: To evaluate the impact of KIT D816 mutation on the salvage therapy in relapsed acute myeloid leukemia (AML) with t(8;21) translocation. Method: The characteristics of the first relapsed AML with t(8;21) translocation from 10 hospitals were retrospectively collected, complete remission (CR(2)) rate after one course salvage chemotherapy and the relationship between KIT mutation and CR(2) rate was analyzed. Results: 68 cases were enrolled in this study, and 30 cases (44.1%) achieved CR(2). All patients received KIT mutation detection, and KIT D816 mutation was identified in 26 cases...
June 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Hong Fang, Rhett P Ketterling, Curtis A Hanson, Animesh Pardanani, Paul J Kurtin, Dong Chen, Patricia T Greipp, Matthew T Howard, Rebecca L King, Daniel L Van Dyke, Kaaren K Reichard
Objectives: Determine ancillary test utilization for the workup of isolated eosinophilia in otherwise morphologically unremarkable bone marrow (BM). Methods: We evaluated BM ancillary testing performed in cases with isolated eosinophilia and otherwise morphologically unremarkable BM. Cases with abnormal morphology (eg, dysplasia, basophilia) and/or findings suggestive of a disorder (eg, unexplained thromboses, lymphoma) are specifically excluded. Results: A total of 132 cases met inclusion criteria...
July 19, 2018: American Journal of Clinical Pathology
Ibrahim Aldoss, Marzia Capelletti, Jihye Park, Romanos Sklavenitis Pistofidis, Raju Pillai, Tracey Stiller, James F Sanchez, Stephen J Forman, Irene M Ghobrial, Amrita Krishnan
Multiple myeloma (MM) patients have an 11-fold increased risk of developing myeloid neoplasms compared to the general population; however, acute lymphoblastic leukemia (ALL) is rarely observed. Given that both MM and the majority of ALL are of B cell origin, this raises the question of whether ALL in patients with MM arises from the same clone. We report 13 cases of B-cell ALL following therapy for MM. The interval from MM diagnosis to ALL onset was 5.4 years (range 3.3-10). The median age at the time of ALL diagnosis was 60 years (range 43-67)...
July 19, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Eva J Gordon, David Parker, Kelly Barth, Jennifer Pena, Julia A Elvin, Thomas DeLeon, Nina J Karlin
Mutations or other alterations in the RET gene have been implicated in a variety of malignancies - most commonly thyroid, but also chronic myelomonocytic leukemia, acute myeloid leukemia, and lung, breast, pancreatic, and colon cancers. Here we present a case of a gentlemen initially diagnosed with and treated for non-small cell lung adenocarcinoma. Genomic profiling of his tumor specimen revealed a RET point mutation with a known association with medullary thyroid cancer (MTC). Further pathological and molecular diagnostic evaluation confirmed a diagnosis of MTC, leading to a change in treatment from standard chemotherapy for non-small cell lung cancer to targeted therapy against RET and potential implications regarding inherited cancer risk for his offspring...
May 2018: Case Reports in Oncology
Lynn Quek, Muriel D David, Alison Kennedy, Marlen Metzner, Michael Amatangelo, Alan Shih, Bilyana Stoilova, Cyril Quivoron, Maël Heiblig, Christophe Willekens, Véronique Saada, Samar Alsafadi, M S Vijayabaskar, Andy Peniket, Oliver A Bernard, Sam Agresta, Katharine Yen, Kyle MacBeth, Eytan Stein, George S Vassiliou, Ross Levine, Stephane De Botton, Anjan Thakurta, Virginie Penard-Lacronique, Paresh Vyas
Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation...
August 2018: Nature Medicine
Patrizia Zappasodi, Laura Marbello, Erika Borlenghi, Monica Fumagalli, Massimo Bernardi, Nicola Fracchiolla, Valentina Mancini, Matteo Da Vià, Emanuele Ravano, Elisa Cerqui, Virginia Valeria Ferretti, Barbara Rocca, Celeste Calvello, Mario Cazzola, Carlo Castagnola, Giuseppe Rossi
Favorable acute myeloid leukemia (AML) patients (pts.) demonstrate a relatively good outcome with standard induction; thus, pts. are generally not addressed to allogeneic transplant in first remission. However, it is not clear if also in a real-life setting, the outcome is homogeneous in the different favorable molecular groups and which are the parameters significantly associated to an increased relapse risk, useful to suggest the need of an intensified approach. In order to clarify this point, we collected clinical data on consecutive unselected AML pts...
July 15, 2018: Annals of Hematology
Elsa Maitre, Philippe Bertrand, Catherine Maingonnat, Pierre-Julien Viailly, Margaux Wiber, Dina Naguib, Véronique Salaün, Edouard Cornet, Gandhi Damaj, Brigitte Sola, Fabrice Jardin, Xavier Troussard
Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. BRAFV600E mutation, detected in more than 80% of the cases, is described as a driver mutation, but additional genetic abnormalities appear to be necessary for the disease progression. For cases of HCL-c harboring a wild-type BRAF gene, the differential diagnosis of the variant form of HCL (HCL-v) or splenic diffuse red pulp lymphoma (SDRPL) is complex. We selected a panel of 21 relevant genes based on a literature review of whole exome sequencing studies ( BRAF , MAP2K1 , DUSP2 , MAPK15 , ARID1A , ARID1B , EZH2 , KDM6A , CREBBP , TP53 , CDKN1B , XPO1 , KLF2 , CXCR4 , NOTH1 , NOTCH2 , MYD88 , ANXA1 , U2AF1 , BCOR , and ABCA8 )...
June 22, 2018: Oncotarget
Pinkal Desai, Nuria Mencia-Trinchant, Oleksandr Savenkov, Michael S Simon, Gloria Cheang, Sangmin Lee, Michael Samuel, Ellen K Ritchie, Monica L Guzman, Karla V Ballman, Gail J Roboz, Duane C Hassane
The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women's Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML...
July 2018: Nature Medicine
Wenwen Ding, Danni Li, Chao Zhuang, Pingping Wei, Wenfeng Mou, Lei Zhang, Hui Liang, Yong Liu
RATIONALE: The JAK2 V617F mutation is frequently found in ET, while it is rare in de novo AML. ET has a low frequency of leukemic transformation. Both secondary AML (sAML) from ET and AML with JAK2 V617F mutation have poor prognoses. Because of the low incidence of JAK2 mutation in acute myeloid leukemia (AML), the clinical features of AML with JAK2 mutation are rarely reported so far, either transformed from essential thrombocythemia (ET) or de novo AML. PATIENT CONCERNS: In this article, we present a pediatric AML patient with the JAK2 V617F mutation...
July 2018: Medicine (Baltimore)
Susan Branford, Paul Wang, David T Yeung, Daniel Thomson, Adrian Purins, Carol Wadham, Nur Hezrin Shahrin, Justine E Marum, Nathalie Nataren, Wendy T Parker, Joel Geoghegan, Jinghua Feng, Naranie Shanmuganathan, Martin C Mueller, Christian Dietz, Doris Stangl, Zoe Donaldson, Haley Altamura, Jasmina Georgievski, Jodi Braley, Anna Brown, Christopher Hahn, Ieuan Walker, Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park, Dong-Wook Kim, Deborah L White, Agnes S M Yong, David M Ross, Hamish S Scott, Andreas W Schreiber, Timothy P Hughes
Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole exome sequencing, copy number variation and/or RNA-Seq for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six chronic phase patients with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15/27 patients (56%) with subsequent BC or poor outcome and in 3/19 optimal responders (16%), P=.007. Frequently mutated genes at diagnosis were ASXL1 , IKZF1 and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene...
July 2, 2018: Blood
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