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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...
June 9, 2017: Cytogenetic and Genome Research
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
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
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
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
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...
June 10, 2016: Hematological Oncology
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
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
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
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
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
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
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
Rebecca L Wright, Katherine K Slemmons, Andrew T M Vaughan
Epidemiological data have linked birth control formulations to an increased risk of infant acute leukemia involving MLL rearrangements. Reverse transcription polymerase chain reaction (RT-PCR) studies showed that 10 nM estradiol enhanced MLL transcription in addition to its common translocation partners, MLLT2 (AF4) and MLLT3 (AF9). The same concentration of estradiol triggered MLL and MLLT3 co-localization without affecting the interaction of genes located on the same chromosomes. Estradiol also stimulated the generation of MLL-MLLT3 fusion transcripts as seen by RT-PCR...
May 2015: Leukemia & Lymphoma
Suellen Valadares Moura, Francianne Andrade, Isis Q Magalhães, Imaruí Costa, Denise Bousfield Silva, Maria Lydia D'Andrea, Vitória P Pinheiro, Maria Lucia M Lee, Fernando Werneck, Mariana Emerenciano, Maria S Pombo-de-Oliveira
The clinical and molecular findings of 77 cases of neonatal leukemia (NL) and 380 of infant leukemia (IL) were selected to distinguish features between NL and IL. Somatic gene mutations associated with acute leukemia including FLT3, RAS and PTPN11 were revisited. There were 42 cases of congenital leukemia associated with Down syndrome (DS) and 39 of these cases presented features of acute myeloid leukemia (AML)-M7. Twenty-seven of the DS cases underwent spontaneous remission and were reclassified as a transient myeloproliferative disorder...
April 2015: Leukemia & Lymphoma
J-H Lim, S Jang, C-J Park, H-S Chi, J-O Lee, E-J Seo
INTRODUCTION: The rearrangement of the mixed-lineage leukemia (MLL) gene occurs through translocations and insertions involving a variety of partner chromosome genes. However, there are few studies on aberrant MLL signal patterns such as concurrent 3' MLL deletion. METHODS: A total of 84 patients with acute leukemia (AL) who had MLL rearrangements detected by florescence in situ hybridization (FISH) were enrolled in the study. The distribution of MLL fusion partner genes was analyzed, and aberrant MLL signals were evaluated...
October 2014: International Journal of Laboratory Hematology
Mariana Emerenciano, Thayana Conceição Barbosa, Bruno Almeida Lopes, Caroline Barbieri Blunck, Alessandra Faro, Camilla Andrade, Claus Meyer, Rolf Marschalek, Maria S Pombo-de-Oliveira
BACKGROUND: Acute leukemia in early age (EAL) is characterized by acquired genetic alterations such as MLL rearrangements (MLL-r). The aim of this case-controlled study was to investigate whether single nucleotide polymorphisms (SNPs) of IKZF1, ARID5B, and CEBPE could be related to the onset of EAL cases (<24 months-old at diagnosis). METHODS: The SNPs (IKZF1 rs11978267, ARID5B rs10821936 and rs10994982, CEBPE rs2239633) were genotyped in 265 cases [169 acute lymphoblastic leukemia (ALL) and 96 acute myeloid leukaemia (AML)] and 505 controls by Taqman allelic discrimination assay...
2014: BMC Cancer
Katrin K Fleischmann, Philipp Pagel, Irene Schmid, Adelbert A Roscher
BACKGROUND: The translocation t(9;11)(p22;q23) leading to the leukemogenic fusion gene MLL-AF9 is a frequent translocation in infant acute myeloid leukemia (AML). This study aimed to identify genes and molecular processes downstream of MLL-AF9 (alias MLL-MLLT3) which could assist to develop new targeted therapies for such leukemia with unfavorable prognosis. METHODS: In the AML cell line THP1 which harbors this t(9;11) translocation, endogenous MLL-AF9 was silenced via siRNA while ensuring specificity of the knockdown and its efficiency on functional protein level...
2014: Molecular Cancer
Bhavna Malik, Charles S Hemenway
AF9 is known to interact with multiple proteins including activators and repressors of transcription. Our data indicate that other AF9 binding proteins compete with the histone methyltransferase DOT1L for AF9 binding thus diminishing its ability to methylate lysine 79 of histone 3. Specifically, we show that AF9 is part of a protein multimer containing members of Polycomb group (PcG) PRC1 complex, CBX8, RING1B, and BMI1. Interaction with CBX8 precludes AF9-DOT1L binding. Knockdown of CBX8 with short-hairpin RNA (shRNA) leads to decreased expression of the AF9 target gene ENaCα...
September 17, 2013: FEBS Letters
Lotte Abildgaard, Hans Beier Ommen, Birgitte Lausen, Henrik Hasle, Charlotte Guldborg Nyvold
OBJECTIVES: Patients with acute myeloid leukaemia (AML) of the monocytic lineage often lack molecular markers for minimal residual disease (MRD) monitoring. The MLL-MLLT3 fusion transcript found in patients with AML harbouring t(9;11) is amenable to RT-qPCR quantification but because of the heterogeneity of translocation break points, the MLL-MLLT3 fusion gene is a challenging target. We hypothesised that MRD monitoring using MLL-MLLT3 as a RT-qPCR marker is feasible in the majority of patients with t(9;11)-positive AML...
November 2013: European Journal of Haematology
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