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Leukemia And Mutation And Diagnosis

Nicole A McNeer, John Philip, Heather Geiger, Rhonda E Ries, Vincent-Philippe Lavallée, Michael Walsh, Minita Shah, Kanika Arora, Anne-Katrin Emde, Nicolas Robine, Todd A Alonzo, E Anders Kolb, Alan S Gamis, Malcolm Smith, Daniela Se Gerhard, Jaime Guidry-Auvil, Soheil Meshinchi, Alex Kentsis
Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10...
February 13, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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
Rebecca A Myers, Scott Wirth, Sherry Williams, Patrick J Kiel
Acute myeloid leukemia (AML) is a hematologic malignancy that affects predominantly older patients, with a median age of diagnosis around 67. Overall prognosis is poor; however, novel targeted therapies that can potentially improve outcomes in these patients have emerged in recent years. Mutations in isocitrate dehydrogenase (IDH) occur in 20% of AML diagnoses. IDH2 performs a crucial role in cellular metabolism, and when this enzyme is inhibited, the cell cannot rid itself of endogenous products and is thus marked for apoptosis...
May 2018: Journal of the Advanced Practitioner in Oncology
Yuan-Yuan Zhang, Xiao-Dong Mo, Xiao-Hui Zhang, Lan-Ping Xu, Yu Wang, Chen-Hua Yan, Huan Chen, Yu-Hong Chen, Wei Han, Feng-Rong Wang, Jing-Zhi Wang, Yu-Qian Sun, Kai-Yan Liu, Xiao-Jun Huang
Acute myelogenous leukemia (AML) patients with fetal liver tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs) have poor prognoses if treated with chemotherapy only, primarily as they experience increased relapse rates. To determine whether this alteration also affects outcomes after haploidentical donor (HID) allogeneic hematopoietic stem cell transplantation (allo-HSCT), we compared 334 consecutive FLT3-ITD-positive vs -negative patients with AML (other than acute promyelocytic leukemia) who underwent HID-HSCT...
February 1, 2019: Bone Marrow Transplantation
Mahesh Swaminathan, Sarah A Bannon, Mark Routbort, Kiran Naqvi, Tapan M Kadia, Koichi Takahashi, Yesid Alvarado, Farhad Ravandi-Kashani, Keyur P Patel, Richard Champlin, Hagop Kantarjian, Louise Strong, Courtney D DiNardo
Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene TP53 The most common reported leukemia associated with LFS is hypodiploid acute lymphoblastic leukemia, but myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS) are also reported, often in the setting of therapy-related disease. We reviewed the clinicopathologic characteristics including cytogenetics and molecular analysis for seven adult patients with LFS and hematologic malignancies evaluated at the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center...
February 2019: Cold Spring Harbor Molecular Case Studies
Yusuke Yamashita, Akinori Nishikawa, Yoshifumi Iwahashi, Masakazu Fujimoto, Izumi Sasaki, Hiroyuki Mishima, Akira Kinoshita, Hiroaki Hemmi, Nobuo Kanazawa, Kouichi Ohshima, Ken-Ichi Imadome, Shin-Ichi Murata, Koh-Ichiro Yoshiura, Tsuneyasu Kaisho, Takashi Sonoki, Shinobu Tamura
Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm characterized by the systemic infiltration of Epstein-Barr virus (EBV)-associated NK cells, and rapidly progressive clinical course. We report the case of a 45-year-old man with intellectual disability who developed ANKL, and describe the identification of a novel genetic mutation of coiled-coil domain-containing 22 (CCDC22). He presented with persistent fever, severe pancytopenia, and hepatosplenomegary. Following bone marrow aspiration, numerous hemophagocytes were identified...
January 31, 2019: International Journal of Hematology
Vincent Louie Mendiola, You-Wen Qian, Bagi Jana
Background: Chronic neutrophilic leukemia (CNL) is an extremely rare myeloproliferative neoplasm (MPN). Due to the difficulty in its diagnosis, the diagnostic criterion was just recently revised in 2016. CNL is defined as: A clonal disorder with sustained primary neutrophilia, with normal neutrophil maturation, that does not meet other MPN criteria, as well as no identifiable mutations of the PDGFRA, PDGFRB or FGFR1 or PCM1-JAK2 genes, and, either, the presence of a CSF3R mutation, or if absent, the presence of sustained neutrophilia (> 3 months), splenomegaly and no other identifiable cause of reactive neutrophilia including the absence of a plasma cell neoplasm, or, if present, demonstration of myeloid cell clonality by cytogenetics...
September 2018: Case Reports in Oncology
Jean-Christophe Ianotto, Natalia Curto-Garcia, Marie Lauermannova, Deepti Radia, Jean-Jacques Kiladjian, Claire N Harrison
Although it is well known that myeloproliferative neoplasms occur in younger patients, few large cohorts of such patients have been reported. Thus, our knowledge is limited especially for children and young adults about circumstances of diagnosis, outcome and treatment. We performed a systematic review of cases published since 2005, concerning patients aged below 20-years at the time of diagnosis of essential thrombocythemia or polycythemia vera. We identified 396 cases of essential thrombocythemia and 75 of polycythemia vera...
January 24, 2019: Haematologica
Antonio Agraz-Doblas, Clara Bueno, Rachael Bashford-Rogers, Anindita Roy, Pauline Schneider, Michela Bardini, Paola Ballerini, Gianni Cazzaniga, Thaidy Moreno, Carlos Revilla, Marta Gut, Maria G Valsecchi, Irene Roberts, Rob Pieters, Paola De Lorenzo, Ignacio Varela, Pablo Menendez, Ronald W Stam
B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1+ (MLL-AF4+) infant B-cell acute lymphoblastic leukemia remains difficult to model, and the pathogenic contribution in cancer of the reciprocal fusions resulting from derivative translocated-chromosomes remains obscure. Here, a multi-layered genome-wide analyses and validation was performed on a total of 124 de novo infant B-cell acute lymphoblastic leukemias uniformly diagnosed/treated according to Interfant99/06 protocol...
January 24, 2019: Haematologica
Fabienne Kunz, Evangelia Kontopoulou, Katarina Reinhardt, Maren Soldierer, Sarah Strachan, Dirk Reinhardt, Basant Kumar Thakur
Despite high remission rates, almost 25% of patients with AML will suffer relapse 3-5 years after diagnosis. Therefore, in addition to existing diagnostic and MRD detection tools, there is still a need for the development of novel approaches that can provide information on the state of the disease. Extracellular vesicles (EVs), containing genetic material reflecting the status of the parental cell, have gained interest in recent years as potential diagnostic biomarkers in cancer. Therefore, isolation and characterization of blood and bone marrow plasma-derived EVs from pediatric AML patients could be an additional approach in AML diagnostics and disease monitoring...
January 23, 2019: Annals of Hematology
Naval Daver, Richard F Schlenk, Nigel H Russell, Mark J Levis
Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML...
January 16, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Musa Yilmaz, Feng Wang, Sanam Loghavi, Carlos Bueso-Ramos, Curtis Gumbs, Latasha Little, Xingzhi Song, Jianhua Zhang, Tapan Kadia, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Nicholas Short, Guillermo Garcia-Manero, Zeev Estrov, Hagop Kantarjian, Andrew Futreal, Koichi Takahashi, Farhad Ravandi
Late relapse, defined as relapse arising after at least 5 years of remission, is rare and occurs in 1-3% of patients with acute myeloid leukemia (AML). The underlying mechanisms of late relapse remain poorly understood. We identified patients with AML who achieved remission with standard induction chemotherapy and relapsed after at least five years of remission (n = 15). Whole exome sequencing was performed in available bone marrow samples obtained at diagnosis (n = 10), remission (n = 6), and first relapse (n = 10)...
January 16, 2019: Blood Cancer Journal
Mansour Alfayez, Sa A Wang, Sarah A Bannon, Dimitrios P Kontoyiannis, Steven M Kornblau, Jordan S Orange, Emily M Mace, Courtney D DiNardo
Germline mutations in GATA2 are associated with a complex immunodeficiency and cancer predisposition syndrome. Somatic GATA2mut in myeloid malignancies may impart a similar phenotype. We reviewed adult patients with a diagnosis of GATA2mut hematological malignancy who were referred to our HHMC for genetic testing, and identified to have somatic GATA2mut . Nine patients with a median age of 63 years were included. Six patients (66.7%) were males. Atypical CML and acute myeloid leukemia were the most common initial presentation...
January 16, 2019: Leukemia & Lymphoma
Annette K Brenner, Elise Aasebø, Maria Hernandez-Valladares, Frode Selheim, Frode Berven, Ida-Sofie Grønningsæter, Sushma Bartaula-Brevik, Øystein Bruserud
Acute myeloid leukemia (AML) is an aggressive malignancy, which is highly heterogeneous with regard to chemosensitivity and biological features. The AML cell population is organized in a hierarchy that is reflected in the in vitro growth characteristics, with only a minority of cells being able to proliferate for more than two weeks. In this study, we investigated the ability of AML stem cells to survive and proliferate in suspension cultures in the presence of exogenous mediators but without supporting non-leukemic cells...
January 10, 2019: Cancers
Ami Chitalia, David M Swoboda, Justine N McCutcheon, Metin Ozdemirli, Nadia Khan, Bruce D Cheson
Richter transformation (RT) is a progression from chronic lymphocytic leukemia (CLL) to a more aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL). Due to the rarity of the disease, data regarding the molecular profile and cell of origin (COO) of RT is limited. We performed immunohistochemistry analysis for COO determination and next-generation sequencing for gene mutation analysis in 11 RT patients. Seventy-nine percent of our patients were classified as non-GCB phenotype. Of the 57 unique mutations identified, the three most commonly mutated genes were TP53, TET2, and CREBBP...
January 11, 2019: Leukemia & Lymphoma
Laurane Cottin, Jérémie Riou, Françoise Boyer, Anne Bouvier, Alain Zannetti, Anaïse Blouet, Matgorzata Truchan-Graczyk, Rébecca Jouanneau-Courville, Annaëlle Beucher, Bénédicte Ribourtout, Corentin Orvain, Mathilde Hunault-Berger, Odile Blanchet, Valérie Ugo, Damien Luque Paz
Classical Philadelphia-negative myeloproliferative neoplasms include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are characterized by the presence of driver mutations of JAK2, CALR or MPL genes. Overexpression of WT1 is used as a marker of minimal residual disease in acute myeloid leukemia, especially after allogeneic stem cell transplantation (SCT). We investigated WT1 expression at diagnosis in 152 MPN patients and showed that the WT1 transcript was overexpressed in PMFs and PVs compared to controls...
December 20, 2018: Blood Cells, Molecules & Diseases
Stefania Stella, Michele Massimino, Elena Tirrò, Silvia Rita Vitale, Luca Scalise, Salvatore Leotta, Maria Stella Pennisi, Adriana Puma, Chiara Romano, Fabio Stagno, Giuseppe Sapienza, Giuseppe Milone, Livia Manzella
BACKGROUND/AIM: The Philadelphia chromosome is found in 30% of acute lymphoblastic leukemia (ALL) patients, a distinct ALL subgroup where the BCR-ABL fusion gene is associated with poor prognosis. Treatment with tyrosine kinase inhibitors (TKIs) often induces complete remission and these patients subsequently undergo an autologous stem cell transplantation (ASCT). However, 20% of subjects experience a relapse associated with the selection of point-mutations in the BCR-ABL kinase domain...
January 2019: Anticancer Research
Jinming Song, Lynn Moscinski, Hailing Zhang, Xiaohui Zhang, Mohammad Hussaini
BACKGROUND: Mutations in splicing factor 3b subunit 1 (SF3B1) have been reported to be associated with a favorable prognosis, while the prognostic impact of tet methylcytosine dioxygenase 2 (TET2) mutations is still controversial. The clinical significance of combined SF3B1 and TET2 mutation is even more uncertain. In this study, the clinical consequences of concurrent double SF3B1/TET2 mutation were compared with isolated SF3B1 or TET2 mutation. MATERIALS AND METHODS: The demographics, diagnosis, cytogenetic abnormalities, and overall survival time of 130 patients with isolated SF3B1 (n=48) or TET2 mutation (n=54), or double SF3B1/TET2 mutation (n=28) were compared by next-generation sequencing...
January 2019: Cancer Genomics & Proteomics
Paola Orsini, Luciana Impera, Elisa Parciante, Cosimo Cumbo, Crescenzio F Minervini, Angela Minervini, Antonella Zagaria, Luisa Anelli, Nicoletta Coccaro, Paola Casieri, Giuseppina Tota, Claudia Brunetti, Alessandra Ricco, Paola Carluccio, Giorgina Specchia, Francesco Albano
BACKGROUND: Alu repeats, belonging to the Short Interspersed Repetitive Elements (SINEs) class, contain about 25% of CpG sites in the human genome. Alu sequences lie in gene-rich regions, so their methylation is an important transcriptional regulation mechanism. Aberrant Alu methylation has been associated with tumor aggressiveness, and also previously discussed in hematological malignancies, by applying different approaches. Moreover, today different techniques designed to measure global DNA methylation are focused on the methylation level of specific repeat elements...
December 22, 2018: Diagnostic Pathology
Keyur P Patel, Roberto Ruiz-Cordero, Wei Chen, Mark J Routbort, Kristen Floyd, Sergio Rodriguez, John Galbincea, Bedia A Barkoh, David Hatfield, Haitham Khogeer, Rashmi Kanagal-Shamanna, C Cameron Yin, Zhuang Zuo, Sanam Loghavi, Chi Young Ok, Courtney D DiNardo, Rajyalakshmi Luthra, L Jeffrey Medeiros
Next-generation sequencing (NGS)-based mutation panels profile multiple genes simultaneously, allowing the reporting of numerous genes while saving labor and resources. However, one drawback of using NGS is that the turnaround time is often longer than conventional single gene tests. This delay can be problematic if molecular results are required to guide therapy in patients with clinically aggressive diseases, such as acute myeloid leukemia. To overcome this limitation, we developed a novel custom platform designated as Ultra-rapid Reporting of GENomic Targets (URGENTseq), an integrated solution that includes workflow optimization and an innovative custom bioinformatics pipeline to provide targeted NGS results on fresh peripheral blood and bone marrow samples within an actionable time period...
January 2019: Journal of Molecular Diagnostics: JMD
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