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Kerstin M Kampa-Schittenhelm, Wichard Vogel, Irina Bonzheim, Falko Fend, Marius Horger, Lothar Kanz, Martin Soekler, Marcus M Schittenhelm
Activating KIT D816V mutations are frequently found in CBF AML, which predicts for an unfavorable outcome. Dasatinib is a potent inhibitor of wildtype and mutant-KIT isoforms - including D816V. We now provide proof of antileukemic efficacy in a patient with relapsing mutant- KIT D816V CBF AML. Importantly, this effect is mediated via overriding the differentiation blockage of the leukemia clone. In addition, we show that dasatinib is capable to induce pulmonary differentiation syndrome - and therefore needs close monitoring of patients under therapy...
February 20, 2018: Oncotarget
Silvia Park, Hangseok Choi, Hee Je Kim, Jae-Sook Ahn, Hyeoung-Joon Kim, Sung-Hyun Kim, Yeung-Chul Mun, Chul Won Jung, Dennis Dong Hwan Kim
The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS...
March 2, 2018: Annals of Hematology
Nicolas Duployez, Elise Boudry-Labis, Christophe Roumier, Nicolas Boissel, Arnaud Petit, Sandrine Geffroy, Nathalie Helevaut, Karine Celli-Lebras, Christine Terré, Odile Fenneteau, Wendy Cuccuini, Isabelle Luquet, Hélène Lapillonne, Catherine Lacombe, Pascale Cornillet, Norbert Ifrah, Hervé Dombret, Guy Leverger, Eric Jourdan, Claude Preudhomme
Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML...
January 19, 2018: Oncotarget
Apollinaire Ngankeu, Parvathi Ranganathan, Violaine Havelange, Deedra Nicolet, Stefano Volinia, Bayard L Powell, Jonathan E Kolitz, Geoffrey L Uy, Richard M Stone, Steven M Kornblau, Michael Andreeff, Carlo M Croce, Clara D Bloomfield, Ramiro Garzon
We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients (n = 61/303; 20%) with respect to age, sex and race matched controls (n = 43/402:11%, P < 0...
January 12, 2018: Oncotarget
Zaw Min Oo, Anuradha Illendula, Jolanta Grembecka, Charles Schmidt, Yunpeng Zhou, Virginie Esain, Wanda Kwan, Isaura Frost, Trista E North, Roger A Rajewski, Nancy A Speck, John H Bushweller
The core binding factor (CBF) gene RUNX1 is a target of chromosomal translocations in leukemia, including t(8;21) in acute myeloid leukemia (AML). Normal CBF function is essential for activity of AML1-ETO, product of the t(8;21), and for survival of several leukemias lacking RUNX1 mutations. Using virtual screening and optimization, we developed Runt domain inhibitors which bind to the Runt domain and disrupt its interaction with CBFβ. On-target activity was demonstrated by the Runt domain inhibitors' ability to depress hematopoietic cell formation in zebrafish embryos, reduce growth and induce apoptosis of t(8;21) AML cell lines, and reduce progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells...
December 18, 2017: Leukemia & Lymphoma
Kerstin Maria Kampa-Schittenhelm, Julia Frey, Lara A Haeusser, Barbara Illing, Ashly A Pavlovsky, Gunnar Blumenstock, Marcus Matthias Schittenhelm
Activating D816 mutations of the class III receptor tyrosine kinase KIT are associated with the majority of patients with systemic mastocytosis (SM), but also core binding factor (CBF) AML, making KIT mutations attractive therapeutic targets for the treatment of these cancers. Crenolanib is a potent and selective inhibitor of wild-type as well as mutant isoforms of the class III receptor tyrosine kinases FLT3 and PDGFRα/β. Notably, crenolanib inhibits constitutively active mutant-FLT3 isoforms resulting from amino acid substitutions of aspartic acid at codon 835, which is homologous to codon 816 in the KIT gene - suggesting sensitivity against mutant-KIT D816 isoforms as well...
October 10, 2017: Oncotarget
Maliha Khan, Jorge Cortes, Wei Qiao, Mohanad A Alzubaidi, Sherry A Pierce, Farhad Ravandi, Hagop M Kantarjian, Gautam Borthakur
PURPOSE: To determine the factors associated with outcomes in patients with core binding factor acute myeloid leukemia (CBF-AML) in first relapse. MATERIAL AND METHODS: We conducted a retrospective analysis of 92 patients with CBF-AML in first relapse who presented to our institution from 1990-2014. Clinical and demographic parameters were included in univariate and multivariate Cox proportional hazards regression model to predict overall survival. RESULTS: Among the 92 relapsed patients, 60 (65%) patients had inv (16) and 32 (35%) had t (8;21)...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
Yuhui Wang, Nan Wu, Duo Liu, Yan Jin
INTRODUCTION: Since the first fusion gene was discovered decades ago, a considerable number of fusion genes have been detected in leukemia. The majority of them are generated through chromosomal rearrangement or abnormal transcription. With the development of techniques, high-throughput sequencing method makes it possible to detect fusion genes systematically in multiple human cancers. Owing to their biological significance and tumor-specific expression, some of the fusion genes are attractive diagnostic tools and therapeutic targets...
October 2017: Current Genomics
Yuichi Ishikawa
Acute myeloid leukemia (AML) is a genetically heterogeneous disease, and its prognosis is stratified on the basis of chromosomal and genetic alterations. Core binding factor (CBF) leukemia consists of AML with t (8;21) (p22;q22) and inv16 (q16q16) /t (16;16) (q16;q16) and is included in AML with recurrent genetic abnormality according to WHO classification. Although CBF-AML is categorized as favorable-risk AML, approximately 40% of patients show relapse. The t (8;21) and inv16 (q16q16) /t (16;16) (q16;q16) result in RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes, respectively; however, the fusion proteins encoded by these genes alone are insufficient for the development of leukemia...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Xi Chen, Hu Dou, Xingjuan Wang, Yi Huang, Ling Lu, Junqing Bin, Yongchun Su, Lin Zou, Jie Yu, Liming Bao
The prevalence and clinical relevance of KIT mutations in childhood core-binding factor (CBF) acute myeloid leukemia (AML) have not been well characterized. In this study, a total of 212 children with de novo AML were enrolled from a Chinese population and 50 (23.5%) of the patients were deemed CBF-AML. KIT mutations were identified in 30% of the CBF-AML cohort. The KIT mutations were clustered in exon 17 and exon 8, and KIT mutations in exons 8 and 17 were correlated with a shorter overall survival (OS) (5-year OS: 30...
August 9, 2017: Leukemia & Lymphoma
Shunsuke Yui, Saiko Kurosawa, Hiroki Yamaguchi, Heiwa Kanamori, Toshimitsu Ueki, Nobuhiko Uoshima, Ishikazu Mizuno, Katsuhiro Shono, Kensuke Usuki, Shigeru Chiba, Yukinori Nakamura, Masamitsu Yanada, Junya Kanda, Kenji Tajika, Seiji Gomi, Keiko Fukunaga, Satoshi Wakita, Takeshi Ryotokuji, Takahiro Fukuda, Koiti Inokuchi
The clinical impact of KIT mutations in core binding factor acute myeloid leukemia (CBF-AML) is still unclear. In the present study, we analyzed the prognostic significance of each KIT mutation (D816, N822K, and other mutations) in Japanese patients with CBF-AML. We retrospectively analyzed 136 cases of CBF-AML that had gone into complete remission (CR). KIT mutations were found in 61 (45%) of the patients with CBF-AML. D816, N822K, D816 and N822K, and other mutations of the KIT gene were detected in 29 cases (21%), 20 cases (15%), 7 cases (5%), and 5 cases (4%), respectively...
October 2017: Annals of Hematology
Clement Chung, Hilary Ma
Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias...
September 2017: Pharmacotherapy
Mario Tiribelli, Antonella Geromin, Margherita Cavallin, Sara Di Giusto, Erica Simeone, Renato Fanin, Daniela Damiani
OBJECTIVE: Overexpression of ABCG2 and CD200 has been independently associated with poor outcome in acute myeloid leukemia (AML). However, no data are available on the role of these two factors in patients with core-binding factor (CBF)-positive or FLT3-negative/NPM1-mutated cytogenetically normal (CN) AML. METHODS: We analyzed 65 adult AML patients with CBF+ (n=16) or FLT3-/NPM1+ CN (n=49), evaluating clinical and biological factors associated with complete remission attainment, leukemia-free survival (LFS) and overall survival (OS)...
September 2017: European Journal of Haematology
Ikuko Omori, Hiroki Yamaguchi, Koichi Miyake, Noriko Miyake, Tomoaki Kitano, Koiti Inokuchi
In core-binding factor acute myeloid leukemia (CBF-AML), there have been conflicting reports regarding the status as an unfavorable prognostic factor of mutation in the KIT gene, the significance of which remains unclear. We previously reported that prognoses differ between the KIT D816V and N822K mutations. In the present study, we compared in vitro the cell-proliferative and anti-apoptotic ability of D816V and N822K. We transduced these KIT mutations into the interleukin-3-dependent cell line TF-1 (TF-1 KIT(D816V), TF-1 KIT(N822K))...
August 2017: Experimental Hematology
Brittany Knick Ragon, Naval Daver, Guillermo Garcia-Manero, Farhad Ravandi, Jorge Cortes, Tapan Kadia, Betul Oran, Maro Ohanian, Alessandra Ferrajoli, Naveen Pemmaraju, Hagop M Kantarjian, Gautam Borthakur
Recurrent translocations, t(8;21) or inv(16), in core binding factor acute myeloid leukemia (CBF-AML) are amenable to monitoring for minimal residual disease (MRD) with reverse transcriptase polymerase chain reaction (RTPCR). Despite a favorable prognosis, disease relapse remains the single cause of treatment failure in CBF-AML. Fusion products of these translocations recruit epigenetic silencing complexes resulting in hematopoietic maturation arrest. We hypothesized that maintenance therapy with hypomethylating agents (HMA), including decitabine (DAC) and azacitidine (AZA) after induction/consolidation, can be used for MRD elimination to ultimately prolong relapse free survival...
September 2017: American Journal of Hematology
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
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 is 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...
March 9, 2017: Blood
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...
April 2017: Biology of Blood and Marrow Transplantation
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)...
June 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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
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