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Leukemia And Mutation And Diagnosis

Hiroshi Moritake
Recently, the modern technique of comprehensive genomic analysis has identified both somatic mutations originating from tumor cells and germline mutations as causative genes of inherited familial leukemias among which Fanconi anemia and Li-Fraumeni syndrome are well known. Pathogenic germline mutations occur in various pathways, affecting DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, neutrophil development, and other critical cellular processes. The clinical manifestations of germline mutations present a wide phenotypic spectrum of patients displaying congenital anomalies, early-onset myelodysplastic syndrome, or no medical problems until the developing leukemia...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Valeria Tosello, Gloria Milani, Annalisa Martines, Nadia Macri, Wouder Van Loocke, Filip Matthijssens, Barbara Buldini, Sonia Minuzzo, Deborah Bongiovanni, Richard Fabian Schumacher, Alberto Amadori, Pieter Van Vlierberghe, Erich Piovan
MYC -translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent MYC -translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis...
October 9, 2018: Cells
Mariam Ibáñez, José Carbonell-Caballero, Esperanza Such, Luz García-Alonso, Alessandro Liquori, María López-Pavía, Marta Llop, Carmen Alonso, Eva Barragán, Inés Gómez-Seguí, Alexander Neef, David Hervás, Pau Montesinos, Guillermo Sanz, Miguel Angel Sanz, Joaquín Dopazo, José Cervera
Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML...
2018: PloS One
Asma Bibi, Shrutika Java, Shruti Chaudhary, Swapnali Joshi, Russel Mascerhenas, Nikhil Rabade, Prashant Tembhare, Papagudi Ganesan Subramanian, Sumeet Gujral, Hari Menon, Navin Khattry, Manju Sengar, Bhausaheb Bagal, Hasmukh Jain, Nikhil Patkar
Background: BRAFV600E mutation has been reported as a unique genetic lesion of hairy cell leukemia (HCL), a subset of which lacks this lesion and shows adverse outcomes. Aims: To determine the prevalence of BRAFV600E in HCL from our center and derive clinicopathological correlation, if any. Materials and Methods: A 9-year retrospective analysis of 46 consecutive cases of HCL diagnosed on morphology and immunophenotyping was done. Stained smears were used as samples for amplification refractory mutation system polymerase-chain reaction using fluorescent primers for mutation detection...
October 2018: Indian Journal of Pathology & Microbiology
Zeba N Singh, Vu H Duong, Rima Koka, Ying Zou, Sameer Sawhney, Li Tang, Maria R Baer, Nicholas Ambulos, Firas El Chaer, Ashkan Emadi
We describe two patients with acute promyelocytic leukemia (APL) with an unusual immunophenotype with co-expression of myeloperoxidase (MPO) with cytoplasmic CD3 (cCD3) representing myeloid and T-lineage differentiation. Both harbored FLT3 -ITD mutations. One additionally had a deletion in the PML gene affecting the primer binding site, thus limiting measurable residual disease (MRD) analysis during follow-up. Both patients achieved durable remission with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapy, thus mitigating the need for repetitive conventional chemotherapy cycles and allogeneic stem cell transplantation...
September 2018: Journal of Hematopathology
Erik Delsing Malmberg, Anna Rehammar, Mariana B Pereira, Jonas Abrahamsson, Tore Samuelsson, Sara Ståhlman, Julia Asp, Anne Tierens, Lars Palmqvist, Erik Kristiansson, Linda Fogelstrand
Minimal residual disease (MRD) in acute myeloid leukemia (AML) is of major prognostic importance. The genetic landscape of AML is characterized by numerous somatic mutations, which constitute potential MRD markers. Leukemia-specific mutations can be identified with exome sequencing at diagnosis and assessed during follow-up at low frequencies using targeted deep sequencing. Our aim was to further validate this patient-tailored assay for substitution mutations. By applying a statistical model, which corrects for position-specific errors, a limit of detection for single nucleotide variations of variant allele frequency (VAF) 0...
September 28, 2018: Journal of Molecular Diagnostics: JMD
Panagiotis Baliakas, Theodoros Moysiadis, Anastasia Hadzidimitriou, Aliki Xochelli, Sabine Jeromin, Andreas Agathangelidis, Mattias Mattsson, Lesley-Ann Sutton, Eva Minga, Lydia Scarfò, Davide Rossi, Zadie Davis, Neus Villamor, Helen Parker, Jana Kotaskova, Evangelia Stalika, Karla Plevova, Larry Mansouri, Diego Cortese, Alba Navarro, Julio Delgado, Marta Larrayoz, Emma Young, Achilles Anagnostopoulos, Karin E Smedby, Gunnar Juliusson, Oonagh Sheehy, Mark Catherwood, Jonathan C Strefford, Niki Stavroyianni, Chrysoula Belessi, Sarka Pospisilova, David Oscier, Gianluca Gaidano, Elias Campo, Claudia Haferlach, Paolo Ghia, Richard Rosenquist, Kostas Stamatopoulos
Chronic lymphocytic leukemia patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinicobiological differences. Considering this, we assessed prognosis separately within mutated and unmutated chronic lymphocytic leukemia in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet-A mutated chronic lymphocytic leukemia patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at 5- and 10-years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively...
September 27, 2018: Haematologica
Imo J Akpan, Afaf E G Osman, Michael W Drazer, Lucy A Godley
PURPOSE OF REVIEW: To review the diagnosis of individuals with hereditary hematopoietic malignancies (HHMs) that predispose to myelodysplastic syndrome and acute myeloid leukemia, barriers to HHM diagnosis, and unaddressed questions and controversies within the HHM field. RECENT FINDINGS: Pathogenic germline mutations in approximately a dozen genes predispose to HHMs, and many more genes are likely to be involved. Many of these HHM genes have only been identified recently...
September 26, 2018: Current Hematologic Malignancy Reports
Paolo K Soriano, Taylor Stone, Junaid Baqai, Sherjeel Sana
BACKGROUND Leukemias and lymphomas can arise from myeloid or lymphoid stem cells. Combined myeloid leukemia and non-Hodgkin's lymphoma (NHL), either synchronous or metachronous, rarely occur in the same patient. This report is of a 67-year-old man with a synchronous diagnosis of both bone marrow chronic myelomonocytic leukemia (CMML) and nodal marginal zone lymphoma (NMZL), which a peripheral low-grade B-cell NHL. CASE REPORT A 67-year-old Caucasian man, who was a long-term cigarette smoker, presented with a five-year history of leukocytosis and cervical lymphadenopathy...
September 26, 2018: American Journal of Case Reports
Fulya Öz Puyan, Serhan Alkan
With increasing characterization of disease associated molecular markers, it is becoming challenging to perform multiple single-gene molecular assays. Specific molecular markers are helpful for diagnostic, prognostic evaluation and management of hematologic malignancies. Introduction and rapid progress on next generation sequencing has led to extensive modifications and offers a novel way to integrate concurrent assessment of multiple target genes in routine laboratory analysis especially in view of increasing clinical demands for testing of multiple genetic aberrations...
September 25, 2018: Balkan Medical Journal
Naomi Kawashima, Akimi Akashi, Yasunobu Nagata, Rika Kihara, Yuichi Ishikawa, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Kunio Kitamura, Emiko Sakaida, Akihiro Takeshita, Hitoshi Suzushima, Tomoki Naoe, Itaru Matsumura, Yasushi Miyazaki, Seishi Ogawa, Hitoshi Kiyoi
We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34...
September 24, 2018: Annals of Hematology
Aline Moignet, Thierry Lamy
Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people...
May 23, 2018: American Society of Clinical Oncology Educational Book
Leslie Naesens, Helena Devos, Friedel Nollet, Lucienne Michaux, Dominik Selleslag
INTRODUCTION: Myeloid sarcoma (MS), previously known as granulocytic sarcoma or chloroma, is a rare neoplastic condition defined as a tumor mass consisting of myeloblasts or immature myeloid cells occurring at an extramedullary site. Clinical presentation is diverse and determined by a tumor mass effect or local organ dysfunction. CASE REPORT: We report the case of a 25-year-old previously healthy male with rapidly progressive shortness of breath. A chest CT scan demonstrated a heterogenous anterosuperior mediastinal mass with pleural and pericardial invasion...
September 18, 2018: Acta Haematologica
Joanna Sobiak, Jolanta Skalska-Sadowska, Maria Chrzanowska, Matylda Resztak, Sylwia Kołtan, Mariusz Wysocki, Jacek Wachowiak
Activity of the enzyme thiopurine methyltransferase (TPMT) determines the anti-leukemic effect of thiopurines used in the chemotherapy of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). TPMT status and its effects on treatment outcome have been studied extensively in ALL and autoimmune disorders, but few data is available on TPMT in AML. The present study assessed the genetic polymorphisms and activity of TPMT in children with AML at different treatment stages, and compared the results with those obtained for children with ALL...
October 2018: Oncology Letters
Karsten Spiekermann, Anne-Sophie Shen
There are several changes in the revised WHO classification for acute leukemia. The latest version of the European Leukemia Network (ELN)-risk classification defines AML with mutations in RUNX1, ASXL1 or TP53 to fall in the unfavorable risk group. Consequently, the somatic molecular genetic testing at the time of initial diagnosis should encompass these before mentioned three genes next to the already routine testing of NPM1, CEBPA and FLT3-ITD. Several new innovative substances have been developed and approved for AML therapy...
September 2018: Deutsche Medizinische Wochenschrift
Elisabeth K M Mack, André Marquardt, Danny Langer, Petra Ross, Alfred Ultsch, Michael G Kiehl, Hildegard I D Mack, Torsten Haferlach, Andreas Neubauer, Cornelia Brendel
Differential induction therapy of all subtypes of Acute Myeloid Leukemia other than Acute Promyelocytic Leukemia is impeded by the long time required to complete complex and diverse cytogenetic and molecular genetic analyses for risk stratification or targeted treatment decisions. Here, we describe a reliable, rapid and sensitive diagnostic approach that combines karyotyping and mutational screening in a single integrated next generation sequencing assay. Numerical karyotyping was performed by low coverage whole genome sequencing followed by copy number variation analysis using a novel algorithm based on in silico-generated reference karyotypes...
September 6, 2018: Haematologica
Felicitas Thol, Razif Gabdoulline, Alessandro Liebich, Piroska Klement, Johannes Schiller, Christian Kandziora, Lothar Hambach, Michael Stadler, Christian Koenecke, Madita Flintrop, Mira Pankratz, Martin Wichmann, Blerina Neziri, Konstantin Büttner, Bennet Heida, Sabrina Klesse, Anuhar Chaturvedi, Arnold Kloos, Gudrun Göhring, Brigitte Schlegelberger, Verena I Gaidzik, Lars Bullinger, Walter Fiedler, Albert Heim, Iyas Hamwi, Matthias Eder, Jürgen Krauter, Richard F Schlenk, Peter Paschka, Konstanze Döhner, Hartmut Döhner, Arnold Ganser, Michael Heuser
Molecular measurable residual disease (MRD) assessment is not established in approximately 60 percent of acute myeloid leukemia (AML) patients due to the lack of suitable markers for quantitative real-time PCR. To overcome this limitation we established an error-corrected next-generation-sequencing (NGS) MRD approach which can be applied to any somatic gene mutation. The clinical significance of this approach was evaluated in 116 AML patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) in complete morphologic remission (CR)...
September 6, 2018: Blood
David P Steensma
Myelodysplastic syndromes (MDS) can be difficult to diagnose, especially when morphological changes in blood and marrow cells are minimal, myeloblast proportion is not increased, and the karyotype is normal. The discovery of more than 40 genes that are recurrently somatically mutated in MDS patients raised hope that molecular genetic testing for these mutations might help clarify the diagnosis in ambiguous cases where patients present with cytopenias and non-diagnostic marrow morphological findings. However, many older healthy individuals also harbor somatic mutations in leukemia-associated driver genes, especially in DNMT3A , TET2 , and ASXL1 - a state termed clonal hematopoiesis of indeterminate potential (CHIP) -- and detection of common aging-associated mutations in a cytopenic patient can cause diagnostic uncertainty...
September 5, 2018: Blood
C Liang, E L Jiang, J F Yao, Y He, R L Zhang, D L Yang, Q L Ma, W H Zhai, Y Huang, J L Wei, S Z Feng, M Z Han
Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of acute myeloid leukemia (AML) patients with FLT3-ITD mutation. Methods: From September 2008 to December 2016, 40 AML patients with FLT3-ITD mutation were enrolled in the study. The therapeutic process, outcomes and prognostic factors were retrospectively analyzed. Results: The median of WBC at initial diagnosis was 35.0 (range 1.7-185.0) ×10(9)/L. The median course number of chemotherapy was 4 (range 2-7)...
August 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Fares Darawshy, Arieh Ben-Yehuda, Karine Atlan, Deborah Rund
Background: Chronic lymphocytic lymphoma (CLL) can be associated with several malignancies, but rarely with myelofibrosis. Only isolated case reports in the literature described the association between CLL and primary myelofibrosis (PMF) in the same patient. Objectives: We describe a case of CLL characterized by the development of PMF and a review of literature. Methods: We describe an 86-year-old female diagnosed as having CLL and followed by the development of splenomegaly and progressively rising LDH levels 27 months later...
2018: Case Reports in Hematology
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