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https://www.readbyqxmd.com/read/29720585/de-novo-activating-mutations-drive-clonal-evolution-and-enhance-clonal-fitness-in-kmt2a-rearranged-leukemia
#1
Axel Hyrenius-Wittsten, Mattias Pilheden, Helena Sturesson, Jenny Hansson, Michael P Walsh, Guangchun Song, Julhash U Kazi, Jian Liu, Ramprasad Ramakrishan, Cristian Garcia-Ruiz, Stephanie Nance, Pankaj Gupta, Jinghui Zhang, Lars Rönnstrand, Anne Hultquist, James R Downing, Karin Lindkvist-Petersson, Kajsa Paulsson, Marcus Järås, Tanja A Gruber, Jing Ma, Anna K Hagström-Andersson
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3 ITD , FLT3 N676K , and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells...
May 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29532520/clinicopathological-characteristics-of-de-novo-and-secondary-myeloid-sarcoma-a-monocentric-retrospective-study
#2
Helena Claerhout, Sophie Van Aelst, Celine Melis, Thomas Tousseyn, Olivier Gheysens, Peter Vandenberghe, Daan Dierickx, Nancy Boeckx
OBJECTIVE: Diagnosing myeloid sarcoma remains challenging, and we aimed to provide clinicopathological features to facilitate diagnosis. METHOD: Clinicopathological data from 41 patients with de novo and 31 with secondary myeloid sarcoma were reviewed. RESULTS: Most de novo cases presented with isolated myeloid sarcoma (n = 19) or myeloid sarcoma with concurrent acute myeloid leukemia (n = 15). Most secondary cases presented after acute myeloid leukemia (n = 11), myeloproliferative neoplasm (n = 9), or myelodysplastic syndrome (n = 8)...
March 12, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29384595/mll-rearranged-acute-myeloid-leukemia-influence-of-the-genetic-partner-in-allo-hsct-response-and-prognostic-factor-of-mll-3-region-mrna-expression
#3
Sergio Burillo-Sanz, Rosario M Morales-Camacho, Teresa Caballero-Velázquez, Estrella Carrillo, Javier Sánchez, Olga Pérez-López, Inmaculada Pérez de Soto, José González Campos, Concepción Prats-Martín, Ricardo Bernal, María Teresa Vargas
OBJECTIVE: MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected gene's expression, in this work, we have studied a cohort of 20 MLL-rearranged acute myeloid leukemia (AML). METHODS: Twenty MLL-rearranged AML patients along with a control cohort of 138 AML patients are included in this work. By RT-PCR and sequencing, MLL genetic fusion was characterized, and relative gene expression quantification was carried out for EVI1, MEIS1, MLL-3', RUNX1, SETBP1, HOXA5, and FLT3 genes...
May 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29164580/mir-564-inhibited-metastasis-and-proliferation-of-prostate-cancer-by-targeting-mllt3
#4
F-J Meng, F-M Meng, H-X Wu, X-F Cao
OBJECTIVE: MiR-564 has been discovered to be abnormally expressed in human malignancy. Two recent studies suggested that miR-564 plays a role in tumor inhibition in both lung and breast cancer. However, no evidence reported the mechanism and function of miR-564 in prostate cancer (PCa). PATIENTS AND METHODS: The PCa tissues and their adjacent normal tissues were collected from 50 PCa patients. Expressions of miR-564 in tissues and cells were evaluated with RT-qPCR...
November 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29133595/targeted-next-generation-sequencing-for-detecting-mll-gene-fusions-in-leukemia
#5
Sadia Afrin, Christine R C Zhang, Claus Meyer, Caedyn L Stinson, Thy Pham, Timothy J C Bruxner, Nicola C Venn, Toby N Trahair, Rosemary Sutton, Rolf Marschalek, J Lynn Fink, Andrew S Moore
Mixed lineage leukemia ( MLL ) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPG) in many patients. Long-distance inverse (LDI)-PCR, the "gold standard" technique that is used to characterize MLL breakpoints, is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted next-generation sequencing (NGS) approach that requires low RNA input was tested...
February 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29105243/multiplex-fusion-gene-testing-in-pediatric-acute-myeloid-leukemia
#6
Yuka Iijima-Yamashita, Hidemasa Matsuo, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Hiroyuki Takahashi, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe
BACKGROUND: Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required. METHODS: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation...
January 2018: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/28871137/c-terminal-bre-overexpression-in-11q23-rearranged-and-t-8-16-acute-myeloid-leukemia-is-caused-by-intragenic-transcription-initiation
#7
A E Marneth, K H M Prange, A S A Al Hinai, S M Bergevoet, N Tesi, E M Janssen-Megens, B Kim, N Sharifi, M L Yaspo, J Kuster, M A Sanders, E C G Stoetman, J Knijnenburg, T C J M Arentsen-Peters, C M Zwaan, H G Stunnenberg, M M van den Heuvel-Eibrink, T Haferlach, M Fornerod, J H Jansen, P J M Valk, B A van der Reijden, J H A Martens
Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues...
March 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28595195/gas6-oncogene-and-reverse-mllt3-kmt2a-duplications-in-an-infant-with-acute-myeloid-leukemia-and-a-novel-complex-hyperdiploid-karyotype-detailed-high-resolution-molecular-cytogenetic-studies
#8
Roberto R Capela de Matos, Daniela R Ney Garcia, Elaine Cifoni, Moneeb A K Othman, Mariana Tavares de Souza, Edna K Carboni, Gerson M Ferreira, Thomas Liehr, Raul C Ribeiro, Maria Luiza M Silva
Pediatric acute myeloid leukemia (AML) is a highly heterogeneous disease, presenting cytogenetic and molecular abnormalities which turned out to be critical prognostic factors. Ploidy changes as gain or loss of individual chromosomes are rare in AML, occurring only in about 1-2% of the affected children. Hyperdiploid karyotypes are exceedingly rare in infants less than 12 months of age. In this age group, structural rearrangements involving the KMT2A gene occur in about 58% of the cases. Among them, the translocation t(9;11)(p22;q23), KMT2A-MLLT3, is the most common abnormality accounting for approximately 22% of KMT2A rearrangements in infant AML cases...
2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28282266/autophagy-is-dispensable-for-kmt2a-mll-mllt3-af9-aml-maintenance-and-anti-leukemic-effect-of-chloroquine
#9
Xiaoyi Chen, Jason Clark, Mark Wunderlich, Cuiqing Fan, Ashley Davis, Song Chen, Jun-Lin Guan, James C Mulloy, Ashish Kumar, Yi Zheng
Recently, macroautophagy/autophagy has emerged as a promising target in various types of solid tumor treatment. However, the impact of autophagy on acute myeloid leukemia (AML) maintenance and the validity of autophagy as a viable target in AML therapy remain unclear. Here we show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared with normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent phagophore (the autophagosome precursor) membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo...
May 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28064313/-biological-microchip-for-establishing-the-structure-of-fusion-transcripts-involving-mll-in-children-with-acute-leukemia
#10
T V Nasedkina, A Yu Ikonnikova, G A Tsaur, A V Karateeva, Yu I Ammour, M A Avdonina, A I Karachunskii, A S Zasedatelev
MLL is involved in fusion genes with more than 100 partner genes, approximately 80 of which have been characterized at the molecular level. MLL fusion genes are often found in infants (60-80% of acute lymphoblastic leukemia (ALL) cases and 40-50% of acute myeloblastic leukemia (AML) cases) and are appreciably rarer (8-10%) in children older than 1 year of age. MLL rearrangements are important markers in diagnosis and treatment choice. To identify the partner gene is of primary importance for prognosis and minimal residual disease monitoring...
November 2016: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/27913458/therapy-related-myeloid-neoplasms-does-knowing-the-origin-help-to-guide-treatment
#11
REVIEW
Michael Heuser
Therapy-related myeloid neoplasms (t-MN) combine t-MDS and therapy related acute myeloid leukemia (t-AML) patients in one entity because of their similar pathogenesis, rapid progression from t-MDS to t-AML, and their equally poor prognosis. Treatment with epipodophyllotoxins like etoposide has been associated with a short interval between treatment and development of t-AML, with fusion oncogenes like KMT2A/MLL-MLLT3 and a better prognosis. In contrast, treatment with alkylating agents has been associated with a longer latency, an initial MDS phase, adverse cytogenetics, and a poor prognosis...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27310306/collaboration-of-mllt1-enl-polycomb-and-atm-for-transcription-and-genome-integrity
#12
REVIEW
Ayako Ui, Akira Yasui
Polycomb group (PcG) repress, whereas Trithorax group (TrxG) activate transcription for tissue development and cellular proliferation, and misregulation of these factors is often associated with cancer. ENL (MLLT1) and AF9 (MLLT3) are fusion partners of Mixed Lineage Leukemia (MLL), TrxG proteins, and are factors in Super Elongation Complex (SEC). SEC controls transcriptional elongation to release RNA polymerase II, paused around transcription start site. In MLL rearranged leukemia, several components of SEC have been found as MLL-fusion partners and the control of transcriptional elongation is misregulated leading to tumorigenesis in MLL-SEC fused Leukemia...
April 25, 2016: Nucleus
https://www.readbyqxmd.com/read/27282883/molecular-characterization-of-kmt2a-fusion-partner-genes-in-13-cases-of-pediatric-leukemia-with-complex-or-cryptic-karyotypes
#13
Daniela R Ney Garcia, Mariana T de Souza, Amanda F de Figueiredo, Moneeb A K Othman, Katharina Rittscher, Eliana Abdelhay, Roberto R Capela de Matos, Claus Meyer, Rolf Marschalek, Marcelo G P Land, Thomas Liehr, Raul C Ribeiro, Maria Luiza Macedo Silva
In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implications. However, the KMT2A partner gene cannot always be identified by banding karyotyping. We sought to identify such partner genes in 13 cases of childhood leukemia with uninformative karyotypes by combining molecular techniques, including multicolor banding FISH, reverse-transcriptase PCR, and long-distance inverse PCR...
December 2017: Hematological Oncology
https://www.readbyqxmd.com/read/26648836/cytogenetic-and-molecular-findings-in-children-with-acute-lymphoblastic-leukemia-experience-of-a-single-institution-in-argentina
#14
Mariela C Coccé, Cristina N Alonso, Jorge G Rossi, Andrea R Bernasconi, Maria A Rampazzi, Maria S Felice, Patricia L Rubio, Silvia Eandi Eberle, Adriana Medina, Marta S Gallego
The purpose of the current study was to evaluate the cytogenetic findings in 1,057 children with acute lymphoblastic leukemia (ALL) referred to the cytogenetics laboratory at the Hospital de Pediatría Dr. Juan P. Garrahan, between 1991 and 2014. Chromosomal abnormalities were evaluated by G-banding and FISH. Since December 2002, RT-PCR determinations were systematically carried out for BCR-ABL1, KMT2A-AFF1, ETV6-RUNX1, and TCF3-PBX1 rearrangements in children, adding KMT2A-MLLT3 and KMT2A-MLLT1 in infants...
October 2015: Molecular Syndromology
https://www.readbyqxmd.com/read/26464168/expression-of-a-passenger-mir-9-predicts-favorable-outcome-in-adults-with-acute-myeloid-leukemia-less-than-60-years-of-age
#15
K Nowek, S M Sun, M K Dijkstra, L Bullinger, H Döhner, S J Erkeland, B Löwenberg, M Jongen-Lavrencic
In double-stranded miRNA/miRNA* duplexes, one of the strands represents an active miRNA, whereas another, known as a passenger strand (miRNA*), is typically degraded. MiR-9* is not detectable in normal myeloid cells. Here we show that miR-9* is expressed in 59% of acute myeloid leukemia (AML) cases and we investigate its clinical impact in 567 adults with de novo AML (age⩽60 years). AML cases with detectable miR-9* included a lower percentage of cases with favorable risk (P<0.001) as compared with those with no detectable miR-9*...
February 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/26215111/heterogeneous-cytogenetic-subgroups-and-outcomes-in-childhood-acute-megakaryoblastic-leukemia-a-retrospective-international-study
#16
Hiroto Inaba, Yinmei Zhou, Oussama Abla, Souichi Adachi, Anne Auvrignon, H Berna Beverloo, Eveline de Bont, Tai-Tsung Chang, Ursula Creutzig, Michael Dworzak, Sarah Elitzur, Alcira Fynn, Erik Forestier, Henrik Hasle, Der-Cherng Liang, Vincent Lee, Franco Locatelli, Riccardo Masetti, Barbara De Moerloose, Dirk Reinhardt, Laura Rodriguez, Nadine Van Roy, Shuhong Shen, Takashi Taga, Daisuke Tomizawa, Allen E J Yeoh, Martin Zimmermann, Susana C Raimondi
Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age ≤18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% ± 2.7% and 49.0% ± 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P = ...
September 24, 2015: Blood
https://www.readbyqxmd.com/read/26159683/prognostic-factors-of-childhood-and-adolescent-acute-myeloid-leukemia-aml-survival-evidence-from-four-decades-of-us-population-data
#17
Md Jobayer Hossain, Li Xie, Emi H Caywood
Growing insight into prognosis of pediatric acute myeloid leukemia (AML) survival has led to improved outcome over time and could be further enhanced through investigation using a large number of patients. To characterize the extent of the association of pediatric AML survival with its identified prognostic factors, we analyzed the United States population-based Surveillance Epidemiology and End Results (SEER) large dataset of 3442 pediatric AML patients diagnosed and followed between 1973 and 2011 using a Cox proportional hazards model stratified by year of diagnosis...
October 2015: Cancer Epidemiology
https://www.readbyqxmd.com/read/25921540/degree-of-recruitment-of-dot1l-to-mll-af9-defines-level-of-h3k79-di-and-tri-methylation-on-target-genes-and-transformation-potential
#18
Aravinda Kuntimaddi, Nicholas J Achille, Jeremy Thorpe, Alyson A Lokken, Ritambhara Singh, Charles S Hemenway, Mazhar Adli, Nancy J Zeleznik-Le, John H Bushweller
The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites and present the nuclear magnetic resonance (NMR) solution structure of a DOT1L-AF9 complex. We generate structure-guided point mutations and find that they have graded effects on recruitment of DOT1L to MLL-AF9...
May 5, 2015: Cell Reports
https://www.readbyqxmd.com/read/25843568/molecular-studies-reveal-a-mll-mllt3-gene-fusion-displaced-in-a-case-of-childhood-acute-lymphoblastic-leukemia-with-complex-karyotype
#19
Daniela Ribeiro Ney Garcia, Thomas Liehr, Mariana Emerenciano, Claus Meyer, Rolf Marschalek, Maria do Socorro Pombo-de-Oliveira, Raul C Ribeiro, Marcelo Gerardin Poirot Land, Maria Luiza Macedo Silva
Rearrangement of the mixed lineage-leukemia gene (MLL-r) is common in hematological diseases and is generally associated with poor prognosis. The mixed-lineage leukemia gene translocated to, 3 (MLLT3) gene (9p22) is a frequent MLL-r partner (∼18% of leukemias with MLL rearrangement) and is characterized by the translocation t(9;11) (p22;q23), forming an MLL-MLLT3 gene fusion. MLL-r are usually simple reciprocal translocations between two different chromosomes, although karyotypes with complex MLL-r have been observed...
April 2015: Cancer Genetics
https://www.readbyqxmd.com/read/25282333/importance-of-a-specific-amino-acid-pairing-for-murine-mll-leukemias-driven-by-mllt1-3-or-aff1-4
#20
Alyson A Lokken, Nicholas J Achille, Ming-Jin Chang, Jeffrey J Lin, Aravinda Kuntimaddi, Benjamin I Leach, Bhavna Malik, Jacqueline B Nesbit, Shubin Zhang, John H Bushweller, Nancy J Zeleznik-Le, Charles S Hemenway
Acute leukemias caused by translocations of the MLL gene at chromosome 11 band q23 (11q23) are characterized by a unique gene expression profile. More recently, data from several laboratories indicate that the most commonly encountered MLL fusion proteins, MLLT1, MLLT3, and AFF1 are found within a molecular complex that facilitates the elongation phase of mRNA transcription. Mutational analyses suggest that interaction between the MLLT1/3 proteins and AFF family proteins are required for experimental transformation of hematopoietic progenitor cells (HPCs)...
November 2014: Leukemia Research
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