scholarly journals Are DNA damage response kinases a target for the differentiation treatment of acute myeloid leukemia?

IUBMB Life ◽  
2018 ◽  
Vol 70 (11) ◽  
pp. 1057-1066
Author(s):  
Rosa Pennisi ◽  
Jacopo Albanesi ◽  
Paolo Ascenzi ◽  
Clara Nervi ◽  
Alessandra di Masi
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Damage Response ◽  
Acute Myeloid

scholarly journals Suppression of the DNA damage response in acute myeloid leukemia versus myelodysplastic syndrome

Oncogene ◽  
2009 ◽  
Vol 28 (22) ◽  
pp. 2205-2218 ◽  
Author(s):  
S Boehrer ◽  
L Adès ◽  
N Tajeddine ◽  
W K Hofmann ◽  
S Kriener ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Damage Response ◽  
Acute Myeloid

scholarly journals Peptide microarray of pediatric acute myeloid leukemia is related to relapse and reveals involvement of DNA damage response and repair

Oncotarget ◽  
2019 ◽  
Vol 10 (45) ◽  
pp. 4679-4690
Author(s):  
Hasan Mahmud ◽  
Arja ter Elst ◽  
Frank J.G. Scherpen ◽  
Tiny Meeuwsen-de Boer ◽  
Kim R. Kampen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Peptide Microarray ◽  
Pediatric Acute Myeloid Leukemia ◽  
Damage Response ◽  
Acute Myeloid

P068 Suppression of the DNA damage response in acute myeloid leukemia versus myelodysplastic syndrome

2009 ◽  
Vol 33 ◽  
pp. S98-S99
Author(s):  
S. Boehrer ◽  
L. Ades ◽  
C. Gardin ◽  
W.K. Hofmann ◽  
P. Fenaux ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Damage Response ◽  
Acute Myeloid

Anlotinib suppresses MLL-rearranged acute myeloid leukemia cell growth through inhibiting SETD1A/AKT-mediated DNA damage response

2020 ◽  
Author(s):  
Jinzhu Chen ◽  
Juan Feng ◽  
Zhihong Fang ◽  
Jing Ye ◽  
Qinwei Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemia Cell ◽  
Xenograft Model ◽  
Gene Set Enrichment Analysis ◽  
Damage Response ◽  
Acute Myeloid

Abstract Background: Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene (MLL) are highly prevalent in hematological malignancy. The poor survival rate and lack of an effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. In this study, we investigated the potential effectiveness and mechanism of Anlotinib, a novel receptor tyrosine kinase inhibitor, in MLL-r acute myeloid leukemia(AML). Methods: MLL-r AML cell lines were treated with different concentration of Anlotinib, then cell viability, apoptosis and cell cycle were analyzed. Next, the anti-leukemia effect of Anlotinib was further evaluated in vivo in a xenograft model of AML-carrying MLL-rearrangement. Finally, we performed RNA-seq analysis, Gene Set Enrichment Analysis (GSEA) and western bolting to explore the underlying mechanism of the anti-leukemia effect of Anlotinib. Results: Our findings revealed that Anlotinib significantly suppresses the growth, promotes robust apoptosis and induces G2/M arrest in MLL-r AML cells. Moreover, Anlotinib effectively inhibited the growth of MLL-r AML cells in a xenograft murine model. In mechanism, we find that the inhibitive role of Anlotinib in MLL-r AML could be largely attributed to the dysfunction of DNA damage and repair. Furthermore, we confirmed that Anlotinib impaired DNA damage response via inhibiting SETD1A and AKT.

scholarly journals Dissecting the Molecular Mechanisms of Aneuploidy in Acute Myeloid Leukemia By Next Generation Sequencing

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1028-1028
Author(s):  
Giorgia Simonetti ◽  
Antonella Padella ◽  
Anna Ferrari ◽  
Viviana Guadagnuolo ◽  
Elisa Zago ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Chromosome Organization ◽  
Single Nucleotide ◽  
Damage Response ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Acute Myeloid Leukemia (AML) is a heterogeneous malignancy characterized by the expansion of myeloid precursor cells with limited or abnormal differentiation capacity. A relatively common event in AML is represented by chromosome gain or loss. Numerical chromosome abnormalities, which define aneuploidy, have a detrimental effect in primary non-malignant cells, since they dramatically reduce cellular fitness. However, evidence suggests that they have a causative role in tumorigenesis and are well tolerated in transformed cells belonging to the myeloid lineage. Aim of the study is to elucidate the pathogenic mechanisms causing and sustaining aneuploidy in AML in order to find novel potential therapeutic targets. A panel of genetic alterations was analyzed on 886 AML cases at Seràgnoli Institute in Bologna between 2002 and 2013. Among them, 31 samples were subjected to whole exome sequencing (WES, Illumina Hiseq2000). Raw data were processed with WES Pipeline web tool for variants detection. Gene expression profiling (GEP, Affymetrix) was performed on bone marrow cells from 49 AML patients at diagnosis with more than 80% blast cells, including 22 aneuploid cases (carrying monosomy, trisomy or a monosomal karyotype) and 27 cases with normal karyotype. The aneuploid status was confirmed by single nucleotide polymorphism (SNP) array. WES analysis of 13 aneuploid and 12 euploid AML cases revealed a significantly higher median value of genetic variants and mutated genes in aneuploid compared with euploid samples (aneuploid vs. euploid: median of variants, 30 vs. 20 (p=0.02) including nonsynonimous single nucleotide variants, frameshift insertions and deletions, stopgains; median of mutated genes, 25 vs. 17 (p=0.05); details will be presented at the meeting). Noticeably, by gene ontology analysis of mutated genes in the aneuploid cohort we observed a strong enrichment in genes regulating cell cycle, including chromosome organization (p=5.4x10-4) and mitotic sister chromatid cohesion (p=6.98x10-4), and chromatin modification (p=1.3x10-4), with most of the variants being not annotated in the COSMIC database. Euploid samples were enriched for mutations affecting genes involved in cytoskeleton (p=1.6x10-3) and metabolic activities (p=1.9x10-3). A number of genes mutated in the aneuploid cases belong to the APCCdc20 complex and localize on chromosomes generally spared by aneuploidy, supporting the key role of the identified aberrations in the molecular mechanisms leading to numerical chromosome abnormalities. Among several mutations predicted as “drivers” by DOTS-Finder tool (CCDC144NL, DNMT3A, GXYLT1, MESP1, TPRX1,TPTE, ZNF717), we defined some candidates involved in cell cycle regulation and DNA replication. Functional analysis are ongoing. Furthermore, a tumor suppressor function was associated with mutated genes involved in the DNA repair process. In our WES analysis, we identified a subgroup of genes linked to DNA damage response, including TP53, which are preferentially mutated in the aneuploid cohort. Since P53 is a limiting-factor in aneuploidy-induced tumorigenesis, we analyzed the mutational status in a larger cohort of AML patients by Next Generation sequencing (NGS) and Sanger sequencing. Interestingly, we identified TP53 mutations in 15/58 aneuploid vs. 1/36 euploid cases (p=3.8x10-3). Finally, differential expression of genes involved in DNA damage and integrity checkpoints was identified by GEP of aneuploid and euploid AML samples. Previous evidence showed that loss of the spindle checkpoint gene BUB1B induces aneuploidy and predisposes to tumorigenesis. Our data, obtained by integrated NGS and GEP approaches, support a causal link between mutations in a panel of genes involved in cell cycle control/chromosome organization and aneuploidy in AML. Genetic and transcriptional alterations of genes regulating DNA damage response were detected in our AML cohort, suggesting novel molecular mechanisms for the acquisition and/or maintenance of the aneuploid condition and consequently, of leukemogenesis. The results indicate that the identified genomic aberrations likely drive chromosome gain and/or loss in AML by cooperating with alterations affecting different pathways, in order to overcome the unfitness barrier induced by aneuploidy. Supported by: FP7 NGS-PTL project, ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12 (L. Bolondi). Disclosures Martinelli: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.

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