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Leukemia And Mutation And Diagnosis

Christian Brieghel, Savvas Kinalis, Christina W Yde, Ane Y Schmidt, Lars Jønson, Michael A Andersen, Caspar da Cunha-Bang, Lone B Pedersen, Christian H Geisler, Finn C Nielsen, Carsten U Niemann
In chronic lymphocytic leukemia, TP53 mutations and deletion of chromosome 17p are well-characterized biomarkers associated with poor progression-free and overall survival following chemoimmunotherapy. Patients harboring low burden TP53 mutations with variant allele frequencies of 0.3-15% have been shown to have similar dismal outcome as those with high burden mutations. We here describe a highly sensitive deep targeted Next Generation Sequencing assay allowing for the detection of TP53 mutations as low as 0...
December 4, 2018: Haematologica
Zhen-Tang Lao, Ling Wen Ding, Omer An, Norimichi Hattori, Qiao-Yang Sun, Kar-Tong Tan, Anand Mayakonda, Wong Gee Chuan, Vikas Madan, De-Chen Lin, Henry Yang, H Phillip Koeffler
Acute leukemia of ambiguous lineage (ALAL) is a rare group of blood cancers that cannot be clearly classified into either myeloid or lymphoid lineage through traditional immunophenotyping (2016 World Health Organization classification). In this study, we performed exome and transcriptome sequencing of 15 diagnosis/relapse samples to identify mutations of this disease. Remarkably, genes involved in DNA repair pathway were frequently mutated and occurred in 80% of the samples. In addition, well known mutations of hematopoietic neoplasms were found in these samples, such as DNMT3A, RUNX1, NOTCH1 and NRAS...
December 4, 2018: Haematologica
Gregory W Roloff, Elizabeth A Griffiths
Mutational profiling has fundamentally changed our approach to patients with acute myeloid leukemia (AML). Patients with AML are routinely profiled for the presence of mutations in FLT3 , NPM1 , CEBPA , and, more recently, TP53 In this chapter, we review the role of mutational profiling to help define disease biology in AML, particularly among patients with putatively intermediate-risk disease. We describe the body of evidence supporting the utility of mutational profiling when performed at the time of diagnosis (to identify prognostic and targetable mutations), at the time of complete remission (to assess minimal residual disease as a marker for relapse), and at the time of relapse (to identify therapeutic targets and eligibility for clinical trials)...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Hong Wang, Tian-Tian Chu, Shi-Yu Han, Jia-Qian Qi, Ya-Qiong Tang, Hui-Ying Qiu, Cheng-Cheng Fu, Xiao-Wen Tang, Chang-Geng Ruan, De-Pei Wu, Yue Han
Cytogenetic and genetic changes have prognostic significance in acute myeloid leukemia (AML). In our study, we compared the cytogenetic changes and gene mutations (NPM1, CEBPA, DNMT3A, FLT3-ITD, FLT3-TKD and C-KIT) with clinical outcome in 1132 AML patients enrolled at our center over 10 years. A total of 977 patients provided gene mutation data: there were subsets of patients who exhibited mutations in NPM1 (17.9%), CEBPA (16.4%), FLT3-ITD (18.5%), FLT3-TKD (3.9%), DNMT3A (8.6%), and C-KIT (8.8%). A total of 557 patients (49...
November 29, 2018: Biology of Blood and Marrow Transplantation
Duval Guillaume, Meytadier Hélène, Bouvard Béatrice
Hematological malignancies can cause bone lesions, of which the most common are the punched-out foci of osteolysis seen in multiple myeloma. However, osteosclerotic lesions are more common. We report the unusual case of a patient with myeloproliferative syndrome in whom the development of osteolytic lesions revealed transformation to acute leukemia. In 2007, this 82-year-old man with essential thrombocythemia since 1994 developed primary polycythemia with the JAK2 mutation V617 F. In July 2017, he was evaluated for an osteolytic lesion in the right humerus with incipient fracturing...
November 21, 2018: Joint, Bone, Spine: Revue du Rhumatisme
Alexander Höllein, Manja Meggendorfer, Frank Dicker, Sabine Jeromin, Niroshan Nadarajah, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach
Acute myeloid leukemia (AML) with NPM1 mutation ( NPM1 mut ) defines a World Health Organization entity. Absence of minimal residual disease (MRD) following induction chemotherapy is associated with an excellent prognosis. Data are conflicting on NPM1 mut AML relapsing with wild-type NPM1 (NPM1 wt ). We analyzed 104 paired samples of NPM1 mut AML patients with relapse and identified 14/104 that relapsed with NPM1 wt AML. Blood counts at diagnosis differed significantly between patients with NPM1 mut and NPM1 wt relapse (median white blood cell count, 30 vs 3 × 109 /L, P = ...
November 27, 2018: Blood Advances
Anne E Bras, Valerie de Haas, Arthur van Stigt, Mojca Jongen-Lavrencic, H Berna Beverloo, Jeroen G Te Marvelde, C Michel Zwaan, Jacques J M van Dongen, Jeanette H W Leusen, Vincent H J van der Velden
BACKGROUND: While it is known that CD123 is normally strongly expressed on plasmacytoid dendritic cells and completely absent on nucleated red blood cells, detailed information regarding CD123 expression in acute leukemia is scarce and, if available, hard to compare due to different methodologies. METHODS: CD123 expression was evaluated using standardized EuroFlow immunophenotyping in 139 pediatric AML, 316 adult AML, 193 pediatric BCP-ALL, 69 adult BCP-ALL, 101 pediatric T-ALL, and 28 adult T-ALL patients...
November 18, 2018: Cytometry. Part B, Clinical Cytometry
Zhihong Hu, C Bueso Ramos, L Jeffrey Medeiros, Chong Zhao, C Cameron Yin, Shaoying Li, Shimin Hu, Wei Wang, Beenu Thakral, Jie Xu, Srdan Verstovsek, Pei Lin
The concurrent presence of JAK2 V617F, monocytosis and bone marrow fibrosis can be observed in both chronic myelomonocytic leukemia (CMML) and primary myelofibrosis (PMF). It can be challenging to distinguish CMML with JAK2 mutation and fibrosis from other myeloid neoplasms, particularly PMF. To identify key features that may help distinguish these two entities, we retrospectively studied 21 cases diagnosed as "CMML" with JAK2 V617F and bone marrow fibrosis that were identified from a cohort of 610 cases of CMML diagnosed during 2006-2016...
November 15, 2018: Human Pathology
Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Takahide Takahashi, Kosuke Tamefusa, Kiichiro Kanamitsu, Kaori Fujiwara, Kana Washio, Takehiro Matsubara, Hirokazu Tsukahara, Masashi Sanada, Akira Shimada
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL...
November 17, 2018: Annals of Hematology
Gregory W Roloff, Elizabeth A Griffiths
Mutational profiling has fundamentally changed our approach to patients with acute myeloid leukemia (AML). Patients with AML are routinely profiled for the presence of mutations in FLT3 , NPM1 , CEBPA , and, more recently, TP53 In this chapter, we review the role of mutational profiling to help define disease biology in AML, particularly among patients with putatively intermediate-risk disease. We describe the body of evidence supporting the utility of mutational profiling when performed at the time of diagnosis (to identify prognostic and targetable mutations), at the time of complete remission (to assess minimal residual disease as a marker for relapse), and at the time of relapse (to identify therapeutic targets and eligibility for clinical trials)...
November 13, 2018: Blood Advances
Asad Ul-Haq, Ming Li Jin, Kwang Won Jeong, Hwan-Mook Kim, Kwang-Hoon Chun
Mixed lineage leukemia proteins (MLL) are the key histone lysine methyltransferases that regulate expression of diverse genes. Aberrant activation of MLL promotes leukemia as well as solid tumors in humans, highlighting the urgent need for the development of an MLL inhibitor. We screened and isolated MLL1-binding ssRNAs using SELEX (<u>S</u>ystemic <u>E</u>volution of <u>L</u>igands by <u>E</u>xponential enrichment) technology. When sequences in sub-libraries were obtained using next-generation sequencing (NGS), the most enriched aptamers-APT1 and APT2-represented about 30% and 26% of sub-library populations, respectively...
November 12, 2018: Biomolecules & Therapeutics
Yi Zhou, Andres Moon, Eric Hoyle, Jonathan R Fromm, Xueyan Chen, Lori Soma, Stephen J Salipante, Brent L Wood, David Wu
BACKGROUND: The presence of measurable residual disease after therapy is a significant risk factor of relapse in patients with acute myeloid leukemia (AML). By detecting cells with leukemia-associated immunophenotype (LAIP), multiparameter flow cytometry (MFC) can detect residual leukemia at a level significantly lower than that detected by morphology. However, changes in LAIPs during or after therapy may pose a challenge to MRD testing. AML with mutated NPM1 represents the largest subtype of AML sharing a common leukemogenic mechanism and similar LAIPs...
November 12, 2018: Cytometry. Part B, Clinical Cytometry
Aneeqa Saif, Syed Faheem Ali Kazmi, Rabia Naseem, Haider Shah, Mohammad Omar Butt
Acute myeloid leukemia (AML) is characterized by the clonal proliferation of malignant myeloid blast cells in the marrow along with impaired normal hematopoiesis. With an almost stagnant approach for the management of patients with AML in the last three decades, the main purpose of this paper is to increase our understanding of recent scientific advancements for the enhanced diagnosis and treatment of AML. Existing research data related to different approaches for a possible improvement in AML management has been collected and discussed...
August 24, 2018: Curēus
Fanghua Ye, Wenwen Chai, Minghua Yang, Min Xie, Liangchun Yang
Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder that involves multiple systems and is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent respiratory infections, and a tendency to develop lymphoid malignancies. A-T is caused by mutations in the ATM gene, with >1,000 mutations reported to date and gradually increasing in number. Patients with A-T have an increased incidence of cancers. The aim of the present study was to retrospectively review the case of a patient who presented at the age of 5 years with cerebellar ataxia without telangiectasia, and was diagnosed with Burkitt leukemia by bone marrow biopsy and molecular testing at the age of 7 years at the Xiangya Hospital of Central South University (Changsha, China)...
November 2018: Molecular and Clinical Oncology
Guilin Tang, John Kennedy Sydney Sir Philip, Olga Weinberg, Wayne Tam, Sam Sadigh, Jonathan I Lake, Elizabeth M Margolskee, Heesun J Rogers, Roberto N Miranda, Carlos Bueso-Ramos C, Eric D Hsi, Attilio Orazi, Robert P Hasserjian, Daniel A Arber, Adam Bagg, Sa A Wang
The purpose of this study is to examine hematopoietic neoplasms with 9p24/JAK2 rearrangement including neoplasms associated with t(8;9)(p22;p24)/PCM1-JAK2 fusion neoplasm as well as cases with translocations involving 9p24/JAK2 and other partner genes. From seven large medical centers, we identified ten patients with t(8;9)(p22;p24) /PCM1-JAK2 and 3 with t(9p24;v)/JAK2 at diagnosis. Majority of the cases showed myeloproliferative neoplasm (MPN) associated features (n = 7) characterized by variable degrees of eosinophilia, myelofibrosis, frequent proliferations of early erythroblasts in bone marrow and extramedullary sites, and infrequent/absent somatic mutations...
November 6, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Paulina Richter-Pechańska, Joachim B Kunz, Beat Bornhauser, Caroline von Knebel Doeberitz, Tobias Rausch, Büşra Erarslan-Uysal, Yassen Assenov, Viktoras Frismantas, Blerim Marovca, Sebastian M Waszak, Martin Zimmermann, Julia Seemann, Margit Happich, Martin Stanulla, Martin Schrappe, Gunnar Cario, Gabriele Escherich, Kseniya Bakharevich, Renate Kirschner-Schwabe, Cornelia Eckert, Martina U Muckenthaler, Jan O Korbel, Jean-Pierre Bourquin, Andreas E Kulozik
We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome-wide chromatin accessibility (ATAC-Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors...
November 2, 2018: EMBO Molecular Medicine
Shunsuke Kimura, Masafumi Seki, Kenichi Yoshida, Yuichi Shiraishi, Masaharu Akiyama, Katsuyoshi Koh, Toshihiko Imamura, Atsushi Manabe, Yasuhide Hayashi, Masao Kobayashi, Akira Oka, Satoru Miyano, Seishi Ogawa, Junko Takita
Molecular mechanisms involved in the relapse of T-cell acute lymphoblastic leukemia (T-ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole exome sequencing in 30 pediatric T-ALL cases, of which 11 diagnosis-relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon-based deep sequencing. NOTCH1/FBXW7 alterations were detected in 73...
November 2, 2018: Cancer Science
Xiaoyan Shao, Dangui Chen, Peipei Xu, Miaoxin Peng, Chaoyang Guan, Pinhao Xie, Cuiying Yuan, Bing Chen
RATIONALE: Philadelphia chromosome positive acute myeloid leukemia (Ph+ AML) is a rare subtype of AML that is now included as a provisional entity in the 2016 revised WHO classification of myeloid malignancies. However, a clear distinction between de novo Ph+ AML and chronic myeloid leukemia blast crisis is challenging. It is still a matter of debate whether Ph+ AML patients should be treated with chemotherapy or tyrosine kinase inhibitors as first-line therapy. PATIENT CONCERNS: We reported here a case of a 46-year-old man who was diagnosed as Ph+ AML...
November 2018: Medicine (Baltimore)
Floris C Loeff, Kevin Rijs, Esther H M van Egmond, Willem H Zoutman, Xiaohang Qiao, Wilhelmina G M Kroes, Sabrina A J Veld, Marieke Griffioen, Maarten H Vermeer, Jacques Neefjes, J H Frederik Falkenburg, Constantijn J M Halkes, Inge Jedema
Adult B-lymphoblastic leukemia (B-ALL) is a hematological malignancy characterized by genetic heterogeneity. Despite successful remission induction with classical chemotherapeutics and novel targeted agents, enduring remission is often hampered by disease relapse due to outgrowth of a pre-existing subclone resistant against the treatment. In this study, we show that small glycophosphatidylinositol (GPI)-anchor deficient CD52-negative B-cell populations are frequently present already at diagnosis in B-ALL patients, but not in patients suffering from other B-cell malignancies...
October 29, 2018: American Journal of Hematology
Sidharth Totadri, Minu Singh, Amita Trehan, Neelam Varma, Prateek Bhatia
Philadelphia (Ph)-like or BCR-ABL like acute lymphoblastic leukemia (ALL) is defined on the basis of a gene expression profile that is similar to Ph-positive ALL. It comprises a wide spectrum of genetic lesions affecting primarily the cytokine receptor and/or kinase signalling genes. It accounts for approximately 10-15% of pediatric ALL, and is more common in patients who are high-risk according to the National Cancer Institute criteria. Presence of Ph-like mutations is an independent predictor of poor outcome...
October 2018: Indian Journal of Hematology & Blood Transfusion
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