Genomic structure and nucleotide sequence of AML1-ETO fusion genes in children with acute myeloid leukemia

2004 ◽  
Vol 216 (03) ◽  
Author(s):  
C Gall ◽  
T Langer ◽  
M Metzler ◽  
S Viehmann ◽  
J Harbott ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nucleotide Sequence ◽  
Myeloid Leukemia ◽  
Genomic Structure ◽  
Fusion Genes ◽  
Acute Myeloid

scholarly journals Occurrence of Acute Myeloid Leukemia in Young Pregnant Women

2008 ◽  
Vol 1 ◽  
pp. CMBD.S823
Author(s):  
Juliane Menezes ◽  
Mariana Emerenciano ◽  
Flávia Pimenta ◽  
Gilson Guedes Filho ◽  
Isis Q. Magalhães ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Women ◽  
Acute Leukaemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Fusion Genes ◽  
Life Threatening ◽  
Poor Outcomes ◽  
Acute Myeloid ◽  
In Pregnancy

Although acute leukaemia is rare in pregnancy its importance lies in its life-threatening potential, both to the child and the mother. The possibility of vertical transmission of leukemic cells increases the attention devoted to these patients and their offspring. Three cases of pregnant young women (15-17 years of age) with AML are presented. This series of cases is the first report where gene abnormalities such as ITD mutations of the FLT3 gene and AML1/ETO fusion genes were screened in pregnant AML patients and their babies, so far. Unfortunately, very poor outcomes have been associated to similar cases described in literature, and the same was true to the patients described herein. Although very speculative, we think that the timing and possible similar exposures would be involved in all cases.

Collaboration of the Meningioma 1 (MN1) Oncogene with MLL-Fusions in Pediatric Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3786-3786
Author(s):  
Ting Liu ◽  
Dragana Jankovic ◽  
Laurent Brault ◽  
Sabine Ehret ◽  
Vincenzo Rossi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Fusion Genes ◽  
Pediatric Leukemia ◽  
Acute Myeloid

Abstract Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic marker in adult acute myeloid leukemia (AML). In pediatric leukemia, we found overexpression of MN1 in 53 of 88 cases: whereas no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL), significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia. Interestingly, 17 of 19 cases harboring fusion genes involving the mixed-lineage leukemia (MLL-X) gene showed elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM-13). In a mouse model of MLL-ENL-induced leukemia we found MN1 to be overexpressed as a consequence of provirus integration. Strikingly co-expression of MN1 with MLL-ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. Immunophenotyping and secondary transplant experiments suggested that MN1 overexpression seems to expand the L-GMP cell population targeted by the MLL-ENL fusion. Gene expression profiling allowed defining a number of potential MN1 hematopoietic targets. Upregulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse acute myeloid leukemia, as well as in pediatric leukemias with elevated MN1 levels. Our work shows that MN1 is overexpressed in a significant fraction of pediatric acute leukemia, is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-ENL most probably through modification of a distinct gene expression program that leads to expansion of a leukemic progenitor population targeted by MLL-fusion genes.

Polymorphisms In Signal Transducer and Activator of Transcription 5 (STAT5) and Response to Cytarabine-Based Chemotherapy In Acute Myeloid Leukemia Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4859-4859
Author(s):  
Bao-An Chen ◽  
Yue-jiao Zhong ◽  
Ji-feng Feng ◽  
Lu Cheng ◽  
Yu-feng Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fusion Genes ◽  
Signal Transducer ◽  
Chinese Sample ◽  
Intermediate Group ◽  
Flight Mass Spectrometry ◽  
Acute Myeloid ◽  
Important Marker

Abstract Abstract 4859 Objectives: Signal transducer and activator of transcription 5 (STAT5) protein is one of the concernful part of STATs families. The constitutive STATs activation has been especially showed in transformation by fusion genes in leukemias. Methods: In this study, we aimed to investigate whether the genetic polymorphisms in the STAT5 gene are associated with the treatment outcomes of Ara-C-based chemotherapy regimens in Acute Myeloid Leukemia (AML) patients. 152 AML patients in a Chinese sample were enrolled in our study. Peripheral blood samples were analyzed by matrix assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF-MS). Results: The results showed that the frequencies of the T/T genotype in rs2293157 and rs1135669 were higher in unfavorable and intermediate group respectively (P=0.023 and P=0.033). The frequency of patients with T/T genotype of rs1135669 was significantly higher in complete remission (CR) group. Conclusions: We concluded that the T/T genotype of rs1135669 might be an important marker for therapeutic efficiency of Ara-C-based chemotherapy in AML patients, especially in Chinese population. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The N6-Adenine Methyltransferase METTL14 Plays an Oncogenic Role in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1536-1536 ◽  
Author(s):  
Huilin Huang ◽  
Hengyou Weng ◽  
Xi Qin ◽  
Boxuan Simen Zhao ◽  
Lou Dore ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Control Group ◽  
Human Leukemia ◽  
Fusion Genes ◽  
Acute Myeloid

Abstract N 6-methyladenosine (m6A) modification is the most abundant internal RNA modification in eukaryotes. Recent studies have shown that the dynamic and reversible regulation of m6A modifications in mRNAs or non-coding RNAs plays critical roles in tissue development, stem cell self-renewal and differentiation, control of heat shock response, and circadian clock controlling, as well as in RNA metabolism and processing. However, little is known about the functions of m6A and m6A regulators in malignant hematopoiesis. METTL14 is a major m6A writer which together with METTL3 forms the core of the methyltransferase complex that catalyzes the conversion of adenosine (A) to m6A. Through qPCR assays, we found that METTL14 was aberrantly up-regulated in mononuclear cells (MNC) from acute myeloid leukemia (AML) patients with t(11q23), t(15;17), or t(8;21) relative to those from healthy donors. To investigate the pathological role of METTL14 in AML, we transduced lineage negative (Lin-) bone marrow (BM) progenitor cells from Mettl14fl/flCreERT mice with MLL-AF9, AML1-ETO9a, or PML-RARa fusion genes and performed colony-forming/replating assays with or without addition of 4-hydroxytamoxifen (4-OHT). Induction of genetic knockout of Mettl14 by 4-OHT treatment remarkably impaired the colony-forming ability of all these AML-related fusion genes after replating. After the first round of plating, we harvested MLL-AF9-transduced cells that were not treated with 4-OHT and transplanted them into lethally irradiated recipient mice. As expected, tamoxifen (TAM) treatment of transplanted mice significantly delayed leukemogenesis compared to mice treated with vehicle (MLL-AF9+TAM, with median survival of 91 days; MLL-AF9+vehicle, with median survival of 71 days; P=0.0012) (Fig.1A). In addition, specific knockdown of Mettl14 with shRNAs showed similar patterns to Mettl14 knockout. Thus our data demonstrate that Mettl14 is crucial for cell transformation and leukemogenesis. Further, to determine the role of Mettl14 in the maintenance of leukemia, we transduced leukemic BM cells from primary MLL-AF9 leukemic mice with shRNAs against Mettl14 or scramble shRNA and transplanted these cells into lethally irradiated recipient mice. Again, a significantly prolonged survival was observed in Mettl14 knockdown groups compared to that in the control group (MLL-AF9+shRNA1, with median survival of 32 days; MLL-AF9+shRNA2, with median survival of 32 days; MLL-AF9+shScramble, with median survival of 23.5 days; P< 0.001 for both knockdown groups) (Fig.1B). Noticeable, mice in Mettl14 knockdown groups showed less c-kit+ cells in BM than mice in the control group (Fig.1C). In addition to the mouse model, we used human leukemia cell lines to investigate the function of METTL14 in human AML cells. Silencing of METTL14 with shRNAs significantly inhibited cell viability, induced apoptosis as well as terminal differentiation of MONOMAC6 and NB4 cell lines (Fig.1D, E, F). Moreover, xenograft model showed that repression of METTL14 significantly inhibited the engraftment of MONOMAC6 cells and thus delayed the onset of leukemia in NSG-SGM3 (NSGS) immunodeficient mice (Fig.1G). Furthermore, knockdown of METTL14 sensitized MONOMAC cells to ATRA or PMA-induced differentiation. Taken together, our results support the oncogenic role of METTL14 in AML and highlight METTL14 as a novel therapeutic target in AML. Figure 1 Oncogenic roles of METTL14 in AML. Figure 1. Oncogenic roles of METTL14 in AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals RNA Sequencing Reveals Novel and Rare Fusion Transcripts in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3627-3627 ◽  
Author(s):  
Antonella Padella ◽  
Giorgia Simonetti ◽  
Giulia Paciello ◽  
Anna Ferrari ◽  
Elisa Zago ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Rna Sequencing ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Fusion Transcript ◽  
Gene Fusions ◽  
Fusion Genes ◽  
Exon 2 ◽  
Frame Fusion ◽  
Acute Myeloid

Abstract Acute Myeloid Leukemia (AML) is a highly heterogeneous disease and a complex network of events contribute to its pathogenesis. Chromosomal rearrangements and fusion genes have a crucial diagnostic, prognostic and therapeutic role in AML. A recent RNA sequencing (RNAseq) study on 179 AML revealed that fusion events occur in 45% of patients. However, the leukemogenic potential of these fusions and their prognostic role are still unknown. To identify novel rare gene fusions having a causative role in leukemogenesis and to identify potential targets for personalized therapies, transcriptome profiling was performed on AML cases with rare and poorly described chromosomal translocations. Bone marrow samples were collected from 5 AML patients (#59810, #20 and #84 at diagnosis and #21 and #32 at relapse). RNAseq was performed using the Illumina Hiseq2000 platform. The presence of gene fusions was assessed with deFuse and Chimerascan. Putative fusion genes were prioritized using Pegasus and Oncofuse, in order to select biologically relevant fusions. Chimeras not supported by split reads, occurring in reactive samples, involving not annotated or conjoined genes were removed. The remaining fusions were prioritized according to mapping of partner genes to chromosomes involved in the translocation or to Chimerascan and deFuse concordance. The CBFβ-MYH11 chimera was identified in sample #84, carrying inv(16) aberration, thus confirming the reliability of our analysis. Sample #59810 carried the fusion transcript ZEB2-BCL11B (Driver Score, DS=0.7), which is an in-frame fusion and a rare event in AML associated with t(2;14)(q21;q32). The breakpoint of the fusion mapped in exon 2 of ZEB2 (ENST00000558170) and exon 2 of BCL11B (ENST00000357195). Differently from previous data, this fusion transcript showed 3 splicing isoforms. Type 1 isoform is the full-length chimera and it retains all exons of both genes involved in the translocation. Type 2 isoform was characterized by the junction of exon 2 of ZEB2 and exon 3 of BCL11B. In type 3 isoform, exon 2 and 3 of BCL11B were removed, resulting in an mRNA composed by exon 2 of ZEB2 and exon 4 of BCL11B. Gene expression profiling showed an upregulation of ZEB2 and BCL11B transcripts in the patient's blasts, compared to 53 AML samples with no chromosomal aberrations in the 14q32 region. The same samples showed the WT1-CNOT2 chimera, which is a novel out-of-frame fusion (DS= 0.008) related to t(11;12) translocation, identified by cytogenetic analysis. Two new in-frame fusion genes were identified in sample #20: CPD-PXT1 (DS=0.07), which appeared as the reciprocal fusion product of t(6;17) translocation, and SAV1-GYPB, which remained cryptic at cytogenetic analysis (DS=0.8, alternative splicing events are being investigated). SAV1 was downregulated in sample #20 compared to our AML cohort, suggesting the putative loss of a tumour-suppressor gene. Sample #21 carried a t(3;12) translocation and RNAseq identified a novel fusion event between chromosomes 19 and 7, involving the genes OAZ and MAFK (DS=0.9). Finally, no chimeras were confirmed in sample #32 having a t(12;18) translocation. Our data suggest that fusion events are frequent in AML and a number of them cannot be detected by current cytogenetic analyses. Gene fusions cooperate to AML pathogenesis and heterogeneity and we are further investigating the oncogenic potential of the identified translocations. Moreover, the results firmly indicate that different approaches, including G-banding, molecular biology, bioinformatics and statistics, need to be integrated in order to better understand AML pathogenesis and improve patients' stratification, High-resolution sequencing analysis currently represent the most informative strategy to tailor personalized therapies. Acknowledgments: ELN, AIL, AIRC, progetto Regione-Università 2010-12 (L. Bolondi), Fondazione del Monte di Bologna e Ravenna, FP7 NGS-PTL project. Disclosures Soverini: Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Martinelli:BMS: Speakers Bureau; MSD: Consultancy; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy.

scholarly journals Whole Transcriptome RNA Sequencing As a Comprehensive Diagnostic Tool for Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2762-2762
Author(s):  
Marieke Griffioen ◽  
Wibowo Arindrarto ◽  
Daniel M. Borras ◽  
Irene J. Locher ◽  
Saskia A.M.E. van Diessen ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Genes ◽  
Genetic Aberrations ◽  
Current Classification ◽  
Whole Transcriptome ◽  
Tandem Duplications ◽  
Acute Myeloid

Abstract Introduction Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of malignant myeloid progenitor cells in the bone marrow that are arrested in differentiation. In AML, genetic aberrations often involve the same genes and play an important role in risk assessment and treatment of AML. In the WHO classification 2016 (Arber et al., Blood 2016), nine AML subtypes of clinical and prognostic importance are distinguished by distinct and practically mutually exclusive mutations, covering 50-60% of AML cases. By analysing an extended panel of genes, Papaemmanuil et al. (NEJM 2016) developed a purely genomic classification of AML. In this system, 11 groups are defined including 6 entities characterized by chromosomal translocations. Similar as in WHO 2016, these 6 entities each account for less than 5% of AML and are identified by metaphase cytogenetics. Of these 6 entities, 5 groups are defined by fusion genes and one group by inv(3)/t(3;3) leading to overexpression of EVI1. The 5 remaining classes include 4 entities with cytogenetically normal AML defined by mutations in NPM1 (27%), bi-allelic CEBPA (4%), genes regulating RNA splicing, chromatin or transcription (18%) and IDH2 R172 mutations (1%) and one entity characterized by mutations in TP53, a complex karyotype or specific aneuploidies (13%). Although the majority of patients can be classified by this new system, 15% of patients still lack class-defining lesions and expression levels of structurally normal genes, which can also have a decisive prognostic impact, are not considered. We propose that whole transcriptome messenger RNA sequencing provides a single and flexible platform to identify the diversity of genetic aberrations relevant for classification of AML. Methods A panel of hundred AML were analysed and HAMLET (Human AMLExpedited Transcriptomics) was developed as bioinformatics pipeline to detect fusion genes, small variants in thirteen genes, long tandem duplications in FLT3 and KMT2A and overexpression of EVI1. In HAMLET, a new algorithm based on soft clipped reads was developed to detect long tandem repeats in FLT3 and KMT2A. All genetic aberrations called by HAMLET were validated by diagnostic data and targeted re-sequencing. Results The data showed that HAMLET correctly called all genetic aberrations relevant for current classification of AML with high sensitivity and specificity. Moreover, the new soft clipped approach that has been integrated in HAMLET proved to be useful not only to detect long tandem duplications in FLT3 and KMT2A, but also to determine the allelic ratio of mutant-to-wild type FLT3, which is predictive for overall survival. By filtering small variants for predicted importance according to large AML sequencing data sets (Jaiswal et al., NEJM 2017), we classified the 100 AML according to genomic classification and showed that 87 cases were classified in single entities, 4 cases in two subgroups and 9 cases had no class-defining lesions. Of the 9 cases without class-defining lesions, 8 cases had detectable driver mutations and one case had no detectable driver mutation. These numbers perfectly match percentages reported by Papaemmanuil et al. (NEJM 2016). Apart from genetic aberrations that are relevant for current classification of AML, HAMLET also identified additional abnormalities. Of particular interest is NUP98-NSD1 (Hollink et al., Blood 2011), a cryptic fusion gene that is missed by metaphase cytogenetics in three AML with no class-defining lesions, and EVI1 overexpression in 5 cases without inv(3)/t(3;3) including three KMT2A-rearranged AML with extremely poor prognosis (Groschel et al., JCO 2013). Conclusions HAMLET correctly called all genetic aberrations relevant for current classification of AML and provides a wealth of additional information with potential consequences for patient management. In conclusion, HAMLET is a comprehensive and reliable pipeline for RNA sequence analysis that may contribute to better risk assessment and personalized treatment of AML. Disclosures Borras: GenomeScan B.V.: Employment. Janssen:GenomeScan B.V.: Employment.

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