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https://www.readbyqxmd.com/read/28299658/clinical-relevance-of-runx1-and-cbfb-alterations-in-acute-myeloid-leukemia-and-other-hematological-disorders
#1
Klaus H Metzeler, Clara D Bloomfield
The translocation t(8;21), leading to a fusion between the RUNX1 gene and the RUNX1T1 locus, was the first chromosomal translocation identified in cancer. Since the first description of this balanced rearrangement in a patient with acute myeloid leukemia (AML) in 1973, RUNX1 translocations and point mutations have been found in various myeloid and lymphoid neoplasms. In this chapter, we summarize the currently available data on the clinical relevance of core binding factor gene alterations in hematological disorders...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28119329/marker-chromosomes-can-arise-from-chromothripsis-and-predict-adverse-prognosis-in-acute-myeloid-leukemia
#2
Tilmann Bochtler, Martin Granzow, Friedrich Stölzel, Christina Kunz, Brigitte Mohr, Mutlu Kartal-Kaess, Katrin Hinderhofer, Christoph E Heilig, Michael Kramer, Christian Thiede, Volker Endris, Martina Kirchner, Albrecht Stenzinger, Axel Benner, Martin Bornhäuser, Gerhard Ehninger, Anthony D Ho, Anna Jauch, Alwin Krämer
Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML are structurally highly abnormal marker chromosomes. In this study we have assessed frequency, cytogenetic characteristics, prognostic impact and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event...
January 24, 2017: Blood
https://www.readbyqxmd.com/read/28089879/clinical-outcome-of-autologous-hematopoietic-cell-transplantation-in-adult-patients-with-acute-myeloid-leukemia-who-may-benefit-from-autologous-hematopoietic-cell-transplantation
#3
Jae-Ho Yoon, Hee-Je Kim, Sung-Soo Park, Young-Woo Jeon, Sung-Eun Lee, Byung-Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min
The role of autologous hematopoietic cell transplantation (auto-HCT) for postremission therapy of acute myeloid leukemia is yet to be elucidated. We retrospectively analyzed 240 patients treated with auto-HCT in first remission. All patients were treated with standard induction chemotherapy, and CD34(+) stem cells were collected at each cycle of consolidation. Stem cells were infused after total body irradiation (1200 cGy), cytarabine (9 g/m(2)), and melphalan (100 mg/m(2)). Estimated 5-year overall survival, disease-free survival (DFS), cumulative incidence of relapse (CIR), and nonrelapse mortality were 58...
January 12, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/27843138/mutations-in-the-ccnd1-and-ccnd2-genes-are-frequent-events-in-adult-patients-with-t-8-21-q22-q22-acute-myeloid-leukemia
#4
A-K Eisfeld, J Kohlschmidt, S Schwind, D Nicolet, J S Blachly, S Orwick, C Shah, M Bainazar, K W Kroll, C J Walker, A J Carroll, B L Powell, R M Stone, J E Kolitz, M R Baer, A de la Chapelle, K Mrózek, J C Byrd, C D Bloomfield
Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a 'second hit' to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well known in CBF-AML but also mutations in the CCND1 and CCND2 genes, which represent novel frequent molecular alterations in AML with t(8;21)...
January 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27798625/the-genomic-landscape-of-core-binding-factor-acute-myeloid-leukemias
#5
Zachary J Faber, Xiang Chen, Amanda Larson Gedman, Kristy Boggs, Jinjun Cheng, Jing Ma, Ina Radtke, Jyh-Rong Chao, Michael P Walsh, Guangchun Song, Anna K Andersson, Jinjun Dang, Li Dong, Yu Liu, Robert Huether, Zhongling Cai, Heather Mulder, Gang Wu, Michael Edmonson, Michael Rusch, Chunxu Qu, Yongjin Li, Bhavin Vadodaria, Jianmin Wang, Erin Hedlund, Xueyuan Cao, Donald Yergeau, Joy Nakitandwe, Stanley B Pounds, Sheila Shurtleff, Robert S Fulton, Lucinda L Fulton, John Easton, Evan Parganas, Ching-Hon Pui, Jeffrey E Rubnitz, Li Ding, Elaine R Mardis, Richard K Wilson, Tanja A Gruber, Charles G Mullighan, Richard F Schlenk, Peter Paschka, Konstanze Döhner, Hartmut Döhner, Lars Bullinger, Jinghui Zhang, Jeffery M Klco, James R Downing
Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML...
December 2016: Nature Genetics
https://www.readbyqxmd.com/read/27795558/expression-of-cd33-is-a-predictive-factor-for-effect-of-gemtuzumab-ozogamicin-at-different-doses-in-adult-acute-myeloid-leukaemia
#6
N Khan, R K Hills, P Virgo, S Couzens, N Clark, A Gilkes, P Richardson, S Knapper, D Grimwade, N H Russell, A K Burnett, S D Freeman
It remains unclear in adult acute myeloid leukaemia (AML) whether leukaemic expression of CD33, the target antigen for gemtuzumab ozogamicin (GO), adds prognostic information on GO effectiveness at different doses. CD33 expression quantified in 1583 patients recruited to UK-NCRI-AML17 (younger adults) and UK-NCRI-AML16 (older adults) trials was correlated with clinical outcomes and benefit from GO including a dose randomisation. CD33 expression associated with genetic subgroups, including lower levels in both adverse karyotype and core-binding factor (CBF)-AML, but was not independently prognostic...
November 15, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27643573/karyotype-plus-npm1-mutation-status-defines-a-group-of-elderly-patients-with-aml-%C3%A2-60-years-who-benefit-from-intensive-post-induction-consolidation-therapy
#7
Wolfgang R Sperr, Otto Zach, Iris Pöll, Susanne Herndlhofer, Paul Knoebl, Ansgar Weltermann, Berthold Streubel, Ulrich Jaeger, Michael Kundi, Peter Valent
Although it is generally appreciated that a subset of elderly patients with acute myeloid leukemia (AML) may benefit from intensive consolidation, little is known about variables predicting such benefit. We analyzed 192 consecutive patients with de novo AML aged ≥60 years who were treated with intensive chemotherapy. About 115 patients (60%) achieved complete hematologic remission (CR). Among several parameters, the karyotype was the only independent variable predicting CR (P < 0.05). About 92% (105/115) of the CR-patients received up to four consolidation cycles of intermediate dose ARA-C...
December 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27613372/prognostic-importance-of-c-kit-mutations-in-core-binding-factor-acute-myeloid-leukemia-a-systematic-review
#8
REVIEW
Hossein Ayatollahi, Arezoo Shajiei, Mohammad Hadi Sadeghian, Maryam Sheikhi, Ehsan Yazdandoust, Masumeh Ghazanfarpour, Seyyede Fatemeh Shams, Sepideh Shakeri
OBJECTIVE/BACKGROUND: Acute myeloid leukemia (AML) is defined as leukemic blast reproduction in bone marrow. Chromosomal abnormalities form different subgroups with joint clinical specifications and results. t(8;21)(q22;q22) and inv(16)(p13;q22) form core binding factor-AML (CBF-AML). c-kit mutation activation occurs in 12.8-46.1% of adults with CBF leukemia. These mutations occur in 20-25% of t(8;21) and 30% of inv(16) cases. METHODS: In this systematic review, we searched different databases, including PubMed, Scopus, and Embase...
March 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/27597292/predictive-value-of-molecular-remissions-postconsolidation-chemotherapy-in-patients-with-core-binding-factor-acute-myeloid-leukemia-cbf-aml-a-single-center-analysis
#9
Uday Deotare, Marwan Shaheen, Joseph M Brandwein, Bethany Pitcher, Suzanne Kamel-Reid, Karen W L Yee, Aaron Schimmer, Mark D Minden, Vikas Gupta, Andre C Schuh
We analyzed the outcome of 80 sequential patients with core binding factor acute myeloid leukemia and evaluated the influence of molecular monitoring by quantitative reverse transcriptase polymerase chain reaction. With a median follow-up of 5 years, the estimated 5-year relapse-free survival and overall survival were 58% and 66%, respectively. Patients who were in molecular remission at the completion of consolidation chemotherapy had a 21% risk of relapse, while the relapse risk for those in molecular remission at the end of 2 years was 5...
September 6, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27512117/bpr1j373-an-oral-multiple-tyrosine-kinase-inhibitor-targets-c-kit-for-the-treatment-of-c-kit-driven-myeloid-leukemia
#10
Li-Tzong Chen, Chiung-Tong Chen, Weir-Torn Jiaang, Tsai-Yun Chen, Joseph H Butterfield, Neng-Yao Shih, John Tsu-An Hsu, Hui-You Lin, Sheng-Fung Lin, Hui-Jen Tsai
Acute myelogenous leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors...
October 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27298396/comparison-of-multiparameter-flow-cytometry-immunophenotypic-analysis-and-quantitative-rt-pcr-for-the-detection-of-minimal-residual-disease-of-core-binding-factor-acute-myeloid-leukemia
#11
COMPARATIVE STUDY
Juan Ouyang, Maitrayee Goswami, Jie Peng, Zhuang Zuo, Naval Daver, Gautam Borthakur, Guilin Tang, L Jeffrey Medeiros, Jeffrey L Jorgensen, Farhad Ravandi, Sa A Wang
OBJECTIVES: To examine the value of minimal residual disease (MRD) by multiparameter flow cytometry (MFC) in core binding factor (CBF) acute myeloid leukemia (AML). METHODS: We studied 42 patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 and 51 with inv(16)(p13.1q22)/CBFB-MYH11 Tandem MRD analyses by MFC and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were performed in 281 bone marrow (BM) samples. RESULTS: Grouping qRT-PCR levels as ≤0...
June 2016: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/27297971/bcr-abl-positive-acute-myeloid-leukemia-a-new-entity-analysis-of-clinical-and-molecular-features
#12
Nina Rosa Neuendorff, Thomas Burmeister, Bernd Dörken, Jörg Westermann
BCR-ABL-positive acute myeloid leukemia (AML) is a rare subtype of AML that is now included as a provisional entity in the 2016 revised WHO classification of myeloid malignancies. Since a clear distinction between de novo BCR-ABL+ AML and chronic myeloid leukemia (CML) blast crisis is challenging in many cases, the existence of de novo BCR-ABL+ AML has been a matter of debate for a long time. However, there is increasing evidence suggesting that BCR-ABL+ AML is in fact a distinct subgroup of AML. In this study, we analyzed all published cases since 1975 as well as cases from our institution in order to present common clinical and molecular features of this rare disease...
August 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27207321/beyond-kit-in-cbf-aml-chromatin-and-cohesin
#13
Rachel E Rau
No abstract text is available yet for this article.
May 19, 2016: Blood
https://www.readbyqxmd.com/read/27140599/feasibility-of-the-aml-profiler-skyline%C3%A2-array-for-patient-risk-stratification-in-a-multicentre-trial-a-preliminary-comparison-with-the-conventional-approach
#14
Josep F Nomdedéu, Eulalia Puigdecanet, Elena Bussaglia, Juan José Hernández, Maite Carricondo, Camino Estivill, Josep Maria Martí-Tutusaus, Mar Tormo, Lurdes Zamora, Elena Serrano, Granada Perea, Maria Paz Queipo de Llano, Antoni García, Isabel Sánchez-Ortega, Josep Maria Ribera, Lara Nonell, Anna Aventin, Francesc Solé, Maria Salut Brunet, Jorge Sierra
Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline™ Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL-PTD, FLT3-ITD and TKD, NPM1 and CEBPAdm mutations...
May 3, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/26980726/comprehensive-mutational-profiling-of-core-binding-factor-acute-myeloid-leukemia
#15
Nicolas Duployez, Alice Marceau-Renaut, Nicolas Boissel, Arnaud Petit, Maxime Bucci, Sandrine Geffroy, Hélène Lapillonne, Aline Renneville, Christine Ragu, Martin Figeac, Karine Celli-Lebras, Catherine Lacombe, Jean-Baptiste Micol, Omar Abdel-Wahab, Pascale Cornillet, Norbert Ifrah, Hervé Dombret, Guy Leverger, Eric Jourdan, Claude Preudhomme
Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group of diseases, and relapse incidence reaches up to 40%. Moreover, translocations involving CBFs are not sufficient to induce AML on its own and the full spectrum of mutations coexisting with CBF translocations has not been elucidated. To address these issues, we performed extensive mutational analysis by high-throughput sequencing in 215 patients with CBF-AML enrolled in the Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor Acute Myeloid Leukemia and Treating Patients with Childhood Acute Myeloid Leukemia with Interleukin-2 trials (age, 1-60 years)...
May 19, 2016: Blood
https://www.readbyqxmd.com/read/26880987/stem-cell-modeling-of-core-binding-factor-acute-myeloid-leukemia
#16
REVIEW
Federico Mosna, Michele Gottardi
Even though clonally originated from a single cell, acute leukemia loses its homogeneity soon and presents at clinical diagnosis as a hierarchy of cells endowed with different functions, of which only a minority possesses the ability to recapitulate the disease. Due to their analogy to hematopoietic stem cells, these cells have been named "leukemia stem cells," and are thought to be chiefly responsible for disease relapse and ultimate survival after chemotherapy. Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) is cytogenetically characterized by either the t(8;21) or the inv(16)/t(16;16) chromosomal abnormalities, which, although being pathognomonic, are not sufficient per se to induce overt leukemia but rather determine a preclinical phase of disease when preleukemic subclones compete until the acquisition of clonal dominance by one of them...
2016: Stem Cells International
https://www.readbyqxmd.com/read/26838606/patient-characteristics-and-outcomes-in-adolescents-and-young-adults-aya-with-acute-myeloid-leukemia-aml
#17
Naveen Pemmaraju, Hagop Kantarjian, Farhad Ravandi, Graciela M Nogueras-Gonzalez, Xuelin Huang, Susan O'Brien, William Wierda, Guillermo Garcia-Manero, Deborah Thomas, Sherry Pierce, Srdan Verstovsek, Gautam Borthakur, Jorge Cortes
BACKGROUND: Little is known about outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA). The purpose of this study is to determine the characteristics and outcomes of AYA AML patients in comparison to older adult patients with AML. PATIENTS AND METHODS: We retrospectively analyzed all AML patients treated at our institution from 1965 to 2009 who were aged 16 to 29 years. RESULTS: Among 3922 adult AML patients treated during this period, 432 (11%) were identified as AYA...
April 2016: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/26681050/additional-chromosomal-abnormalities-in-core-binding-factor-acute-myeloid-leukemia
#18
H H Hsiao, Y C Liu, H C Wang, Y F Tsai, C H Wu, S F Cho, J F Hsu, C T Huang, S Y Hsiao, C P Lee, C S Chang, S F Lin, T C Liu
Despite sharing a similar genetic abnormality, patients with core binding factor acute myeloid leukemia (CBF-AML), which is characterized by the presence of t(8;21) or inv(16)/t(16;16), show heterogeneous survival. Other molecular or cytogenetic factors are supposed to have an impact on the prognosis. We enrolled 24 CBF-AML patients to determine the impact of cytogenetic abnormality, and c-KIT, FLT3, NPM1, and CEBPA mutations on the prognosis. Only three patients had the c-KIT mutation (3/24, 12.5%) and one had the FLT3 mutation...
2015: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/26484088/genome-wide-binding-of-transcription-factors-in-inv-16-acute-myeloid-leukemia
#19
A Mandoli, K Prange, J H A Martens
The inv(16) translocation is associated with 5% of AML cases and gives rise to expression of the oncofusion protein CBFβ-MYH11. Although different molecular mechanisms for the oncogenic activity of this fusion protein have been proposed these were mostly based on in vitro experiments or single loci analysis. Recently, we investigated the genome-wide action of this fusion protein in the context of other hematopoietic transcription factors (Mandoli et al., 2014). Here, we describe in detail the ChIP-seq and RNA-seq methods used to generate the data associated with this study...
December 2014: Genomics Data
https://www.readbyqxmd.com/read/26387755/hdac8-inhibition-specifically-targets-inv-16-acute-myeloid-leukemic-stem-cells-by-restoring-p53-acetylation
#20
Jing Qi, Sandeep Singh, Wei-Kai Hua, Qi Cai, Shi-Wei Chao, Ling Li, Hongjun Liu, Yinwei Ho, Tinisha McDonald, Allen Lin, Guido Marcucci, Ravi Bhatia, Wei-Jan Huang, Chung-I Chang, Ya-Huei Kuo
Acute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16)(+) AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance...
November 5, 2015: Cell Stem Cell
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