Aggressive Aneuploid Acute Myeloid Leukemia Is Dependent on Alterations of P53, Gain of APC and PLK1 and Loss of RAD50

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1702-1702
Author(s):  
Giorgia Simonetti ◽  
Antonella Padella ◽  
Marco Manfrini ◽  
Italo Faria do Valle ◽  
Cristina Papayannidis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Copy Number Loss ◽  
Mutation Load ◽  
Acute Myeloid

Abstract Chromosome number alterations, aneuploidy, is a hallmark of cancer. It occurs in about 15% of acute myeloid leukemia (AML) cases, is generally preserved throughout disease progression (Bochtler et al. Leukemia 2015) and correlates with adverse prognosis (Breems et al. JCO 2008, Papaemmanuil et al. NEJM 2016). This evidence highlights the need of understanding the molecular mechanisms that promote and sustain aneuploidy in AML, in order to define novel potential therapeutic targets. In the NGS-PTL project we profiled the genomic landscape of 536 hematological samples by whole exome sequencing (WES, Illumina). Among them, we analyzed 88 and 68 samples from aneuploid (A-) FLT3-wildtype AML (isolated trisomy and monosomy, complex and monosomal karyotype) and euploid (E-) AML (normal and complex karyotype, <3 abnormalities), respectively (100 bp, paired-end). Variants were called by MuTect and Varscan 2.0. WES output was integrated with genotype data (CytoScan HD Array, Affymetrix and Nexus Copy Number analysis) and gene expression profiling (HTA 2.0 and TAC 3.0, Affymetrix). A-AML showed an increased genomic instability, as confirmed by a higher mutation load compared with E-AML (median number of variants: 22 (range: 2-95) and 11 (range: 3-45), respectively, p<.001), which was associated with increased patients' age (median age of 62 for A-AML and 55 for E-AML, p<.05). The increased age and mutation load correlated with a mutational signature with prominence of C>A substitutions, compared with the C>T transition-related signature, which is prevalent in AML. A-AML was associated with mutations and/or heterozygous deletion of TP53 (p<.001), which co-occurred with copy number loss of both the tumor suppressor APC and the DNA repair gene RAD50 in 93% of cases (p<.001). Moreover, A-AML was enriched for a gene expression signature of p53-deficiency, independently of TP53 structural defects (p<.05, GSEA). Mutations and deregulated expression of genes involved in cell cycle contributed to the A-AML phenotype, with 68% A-AML vs. 32% E-AML patients (p<.01) carrying at least one genomic lesion affecting the process. The alterations targeted the following pathways: DNA repair (i.e. reduced RAD50 expression, p<.001), cell cycle checkpoints (i.e. mutated CHK2), regulation of PLK1 activity at G2/M transition (i.e. mutation and 2-fold upregulation of PLK1, p<.01), mitotic metaphase and anaphase (i.e. increased CDC20 level, p<.001) and separation of sister chromatids (i.e. mutated BUB1B, ESPL1, CENPO). Of note, a 3-gene signature composed of PLK1, CDC20 and RAD50, was able to discriminate 73% of patients between the A- and E-AML cohorts. This signature was confirmed at protein level. In parallel, E-AML showed a preferential dependency on epigenetic mechanisms, with recurrent genomic lesions of ASXL1/2, BCOR/L1, EZH2 and MLL, enrichment of FLT3 alterations and mutations activating RAS signal transduction (p<.05). Of note, a HOX-related signature characterized by overexpression of the HOX family members HOXA7, HOXB3 and MEIS1 identified E-AML. We show here for the first time the molecular mechanisms promoting and maintaining aneuploidy in AML. Our results indicate that p53 deficiency, either caused by somatic mutations, copy number loss, impaired DNA damage response and enhanced PLK1 signaling synergize with APCgain, RAD50 structural or functional loss and forced progression through mitosis, to override cell cycle and mitotic checkpoints and allow the formation of daughter cells with an aberrant chromosome number. These mechanisms cooperate with recurrent mutations of genes involved in protein ubiquitination and proteasome-mediated protein catabolic process in A-AML, indicative of the attempt of aneuploid cells to override the proteotoxic stress due to the unbalanced protein load generated by the aneuploid condition. This evidence provides the rationale for exploiting proteasome inhibition (Velcade), p53 reactivation (MDM2/4 inhibitor) and targeting of the cell cycle (CHK1/2 inhibitor) downstream to p53 (WEE1 inhibitor) as strategies for novel combination therapies against aggressive aneuploid AML, which are under clinical investigation in our Institution and may serve as a model for aneuploid tumors. GS and AP: equal contribution. Supported by: FP7 NGS-PTL project, ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12 (L. Bolondi). Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Martinelli:Ariad: Consultancy, Speakers Bureau; MSD: Consultancy; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Genentech: Consultancy; Novartis: Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

MicroRNA-29a Is An Oncogene in Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 683-683
Author(s):  
Christopher Y. Park ◽  
Yoon-Chi Han ◽  
Govind Bhagat ◽  
Jian-Bing Fan ◽  
Irving L Weissman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Hematopoietic Stem Cells ◽  
Mirna Expression ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract microRNAs (miRNAs) are short, non-protein encoding RNAs that bind to the 3′UTR’s of target mRNAs and negatively regulate gene expression by facilitating mRNA degradation or translational inhibition. Aberrant miRNA expression is well-documented in both solid and hematopoietic malignancies, and a number of recent miRNA profiling studies have identified miRNAs associated with specific human acute myeloid leukemia (AML) cytogenetic groups as well as miRNAs that may prognosticate clinical outcomes in AML patients. Unfortunately, these studies do not directly address the functional role of miRNAs in AML. In fact, there is no direct functional evidence that miRNAs are required for AML development or maintenance. Herein, we report on our recent efforts to elucidate the role of miRNAs in AML stem cells. miRNA expression profiling of AML stem cells and their normal counterparts, hematopoietic stem cells (HSC) and committed progenitors, reveals that miR-29a is highly expressed in human hematopoietic stem cells (HSC) and human AML relative to normal committed progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors is sufficient to induce a myeloproliferative disorder (MPD) that progresses to AML. During the MPD phase of the disease, miR-29a alters the composition of committed myeloid progenitors, significantly expedites cell cycle progression, and promotes proliferation of hematopoietic progenitors at the level of the multipotent progenitor (MPP). These changes are manifested pathologically by marked granulocytic and megakaryocytic hyperplasia with hepatosplenomegaly. Mice with miR-29a-induced MPD uniformly progress to an AML that contains a leukemia stem cell (LSC) population that can serially transplant disease with as few as 20 purified LSC. Gene expression analysis reveals multiple tumor suppressors and cell cycle regulators downregulated in miR-29a expressing cells compared to wild type. We have demonstrated that one of these genes, Hbp1, is a bona fide miR-29a target, but knockdown of Hbp1 in vivo does not recapitulate the miR-29a phenotype. These data indicate that additional genes are required for miR-29a’s leukemogenic activity. In summary, our data demonstrate that miR-29a regulates early events in normal hematopoiesis and promotes myeloid differentiation and expansion. Moreover, they establish that misexpression of a single miRNA is sufficient to drive leukemogenesis, suggesting that therapeutic targeting of miRNAs may be an effective means of treating myeloid leukemias.

The Role of TWIST1 Gene Expression and Hypoxic Microenvironment in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3839-3839
Author(s):  
Emilia Carolina Malafaia ◽  
A. Mario Marcondes ◽  
Ekapun Karoopongse ◽  
Daniele Serehi ◽  
Maria de Lourdes L. F. Chauffaille ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Twist1 Expression ◽  
Disease Biology ◽  
Acute Myeloid

Abstract TWIST1, a basic helix-loop-helix (bHLH) transcription factor, plays a critical role in mesodermal development and organogenesis. Overexpressed TWIST1 has been thoroughly related to epithelial-mesenchymal transition (EMT) in solid tumors (QIN Q et al., 2012) and has been described as an emerging risk factor in hematological neoplasms (MERINDOL et al., 2014). . Many questions remain to be addressed concerning to the role of TWIST1 in acute myeloid leukemia (AML). The understanding of TWIST1 in leukemia cells and its interaction with microenvironment can offer new insights in regards to disease biology and therapeutic targets for patients with AML. Objectives: 1) to evaluate the role of stroma contact and hypoxia in TWIST1 expression in myeloid cell lines. 2) To evaluate the functional impact of overexpressing TWIST1 on KG1a and PL21 cells. 3) To evaluate TWIST1 expression in primary cells of AML patients. Methods: In order to mimic bone marrow microenvironment, myeloid cells were co-cultured with mesenchymal HS5 cell line and PO2 1% was established with Smart -Trak¨ 2 (Sierra Instruments, Inc.) equipment. Quantitative mRNA was determined using TaqMan¨ Universal Master Mix (Applied Biosystems, Foster City, CA) and 3-step standard cycling conditions with sequence-specific primer TWIST1 normalized to the expression of β-actin. KG1a and PL21 cells were transduced with lentivirus vector carrying e-GFP ("enhanced green fluorescence protein") for stable expression of TWIST1. Transduced cells were sorted by FITC fluorochrome and then verified through western blot analysis with TWIST1 antibody. For quantification of apoptosis, cells were labeled with PE-conjugated antibody using annexin V-phycoerythrin and propidium iodide (BD Biosciences, USA). DAPI (4',6- diamidino-2-phenylindole dihydrochloride) was used to stain DNA and determine cell cycle information . Apoptosis and cell cycle were analyzed by FACS -Becton Dickinson Canto II (BD Biosciences). Statistical analysis was assessed with unpaired t test. Results: Hypoxia induced TWIST1 mRNA expression in OCIAML3, PL21, KG1a and ML1 cell lines (fold-increased 46.3, 29.8, 12.9 and 2.3 respectively). Cells expressing endogenous TWIST1 protein (OCIAML3 and ML1) showed resistance to apoptosis in a hypoxic microenvironment (normoxia versus hypoxia: OCI/AML3, 22.6 % vs 11.7% and ML1, 29.8% vs. 7.5%) in contrast, cells not expressing endogenous TWIST1 protein (KG1a and PL21) went to apoptosis in the same conditions. Thus, overexpressing TWIST1 in KG1a and PL21 induced apoptosis protection in hypoxia (KG1a unmodified vs. modified: 17.6 ± 6.3 vs. 2.8 ± 6.3, p=0.04; PL21 unmodified vs. modified: 26.9 ± 10.9 vs. 3.2 ± 0.6, p=0.04) (fig 1). We found increased TWIST1 mRNA levels in bone marrow samples of 23 AML patients (3.88 ± 1.59) compared with 5 healthy controls (0.54 ±0.25) (p= 0.02) (fig 2). Patients in the highest tertile of TWIST1 expression did not show differences in percentage of blasts in bone marrow and complete remission after treatment compared with patients in low and middle tertile. Conclusion: Our data suggest TWIST1 gene expression protects acute myeloid leukemia cells from apoptosis in a hypoxic microenvironment. Moreover, our results showed increased expression of TWIST1 in AML patients. Thus, TWIST1 is a potential gene involved in leukemogenesis and should be further explored to understand disease biology and potential therapeutic targets. Disclosures No relevant conflicts of interest to declare.

scholarly journals A deconvolution method and its application in analyzing the cellular fractions in acute myeloid leukemia samples

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Huamei Li ◽  
Amit Sharma ◽  
Wenglong Ming ◽  
Xiao Sun ◽  
Hongde Liu
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Bulk Sample ◽  
Marker Genes ◽  
Benchmark Datasets ◽  
Multiple Conditions ◽  
Acute Myeloid

Abstract Background The identification of cell type-specific genes (markers) is an essential step for the deconvolution of the cellular fractions, primarily, from the gene expression data of a bulk sample. However, the genes with significant changes identified by pair-wise comparisons cannot indeed represent the specificity of gene expression across multiple conditions. In addition, the knowledge about the identification of gene expression markers across multiple conditions is still paucity. Results Herein, we developed a hybrid tool, LinDeconSeq, which consists of 1) identifying marker genes using specificity scoring and mutual linearity strategies across any number of cell types, and 2) predicting cellular fractions of bulk samples using weighted robust linear regression with the marker genes identified in the first stage. On multiple publicly available datasets, the marker genes identified by LinDeconSeq demonstrated better accuracy and reproducibility compared to MGFM and RNentropy. Among deconvolution methods, LinDeconSeq showed low average deviations (≤0.0958) and high average Pearson correlations (≥0.8792) between the predicted and actual fractions on the benchmark datasets. Importantly, the cellular fractions predicted by LinDeconSeq appear to be relevant in the diagnosis of acute myeloid leukemia (AML). The distinct cellular fractions in granulocyte-monocyte progenitor (GMP), lymphoid-primed multipotent progenitor (LMPP) and monocytes (MONO) were found to be closely associated with AML compared to the healthy samples. Moreover, the heterogeneity of cellular fractions in AML patients divided these patients into two subgroups, differing in both prognosis and mutation patterns. GMP fraction was the most pronounced between these two subgroups, particularly, in SubgroupA, which was strongly associated with the better AML prognosis and the younger population. Totally, the identification of marker genes by LinDeconSeq represents the improved feature for deconvolution. The data processing strategy with regard to the cellular fractions used in this study also showed potential for the diagnosis and prognosis of diseases. Conclusions Taken together, we developed a freely-available and open-source tool LinDeconSeq (https://github.com/lihuamei/LinDeconSeq), which includes marker identification and deconvolution procedures. LinDeconSeq is comparable to other current methods in terms of accuracy when applied to benchmark datasets and has broad application in clinical outcome and disease-specific molecular mechanisms.

scholarly journals Identification of Prognostic Signature Based on the Copy Number Variation (CNV) and Expression in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Changchun Niu ◽  
Di Wu ◽  
Alexander J. Li ◽  
Kevin H. Qin ◽  
Daniel A. Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Survival Analysis ◽  
Copy Number Variation ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Number Variation ◽  
Acute Myeloid ◽  
Cancer Panel

Abstract Purpose Acute myeloid leukemia (AML) is caused by multiple genetic alterations in the hematopoietic progenitors, and molecular genetic analysis has provided useful information for AML diagnosis and prognosis. However, an integrative understanding about the prognosis value of specific copy number variation (CNV) and CNV-modulated gene expression has been limited. Methods We conducted an integrative analysis of CNV profiling and gene expression using data from the TARGET and TCGA AML cohorts. The CNV data from TCGA were analyzed using the GISTIC. CNV survival analysis and mRNA survival analysis were conducted with the Multivariate Cox proportional hazards regression model using R software with “survminer” and “survival” packages. KEGG cancer panel genes were extracted from the cancer related pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). The R package “circlize” was used for mapping the CNV genes to chromosomes. Results From this investigation, we observed distinct CNV patterns in the AML risk groups as well as the expression of 251 genes significantly modulated by CNV in both cohorts. There were 102 CNV genes (located at 7q31-34, 16q24) associated with clinical outcomes in AML, which were identified in the TARGET cohort and validated in the TCGA cohort, three of which being miRNA genes (MIR29A, MIR183, MIR335) that overlapped with a KEGG cancer panel. Five genes were identified whose expressions were modulated by CNV and significantly associated with clinical outcomes, and among them, the deletion of SEMA4D and CBFB were found to potentially have protective effects against AML. Moreover, the distribution of CNV in these five CNV-modulated genes was independent of the risk groups, which suggests that they are independent prognosis factors. Conclusion Overall, this study identified 102 CNV genes and five CNV-modulated gene expressions that are crucial for developing new modes of prognosis evaluation and target therapy for AML.

scholarly journals Identification of prognostic signature based on the copy number variation (CNV) and expression in acute myeloid leukemia

2021 ◽  
Author(s):  
Changchun Niu ◽  
Di Wu ◽  
Alexander J. Li ◽  
Kevin H. Qin ◽  
Daniel A. Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Survival Analysis ◽  
Copy Number Variation ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Number Variation ◽  
Acute Myeloid ◽  
Cancer Panel

Abstract Background Acute myeloid leukemia (AML) is caused by multiple genetic alterations in the hematopoietic progenitors, and molecular genetic analysis has provided useful information for AML diagnosis and prognosis. However, an integrative understanding of the prognostic value of specific copy number variation (CNV) and CNV-modulated gene expression has been limited. Methods We conducted an integrative analysis of CNV profiling and gene expression using data from the TARGET and TCGA AML cohorts. The CNV data from TCGA were analyzed using the GISTIC and all CNV data by genes on every patient were obtained. CNV survival analysis and mRNA survival analysis were conducted with the Multivariate Cox proportional hazards regression model using R software with “survminer” and “survival” packages. KEGG cancer panel genes were extracted from the cancer-related pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). The R package “circlize” was used for mapping the CNV genes to chromosomes. Results From this investigation, we observed distinct CNV patterns in the AML risk groups as well as the expression of 251 genes significantly modulated by CNV in both cohorts. There were 102 CNV genes (located at 7q31-34, 16q24) associated with clinical outcomes in AML, which were identified in the TARGET cohort and validated in the TCGA cohort, three of which being miRNA genes (MIR29A, MIR183, MIR335) that overlapped with a KEGG cancer panel. Five genes were identified whose expression was modulated by CNV and significantly associated with clinical outcomes, and among them, the deletion of SEMA4D and CBFB were found to potentially have protective effects against AML. The result was also validated with patient marrow samples. Moreover, the distribution of CNV in these five CNV-modulated genes was independent of the risk groups, which suggests that they are independent prognosis factors. Conclusion Overall, this study identified 102 CNV genes and five CNV-modulated gene expression that is crucial for developing new modes of prognosis evaluation and target therapy for AML.

scholarly journals High Expression of Mir-9 down-Regulates the Poor Outcome Prognosticator ERG and Associates with Reduced Relapse-Rates in Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1575-1575 ◽  
Author(s):  
Heike Weidner ◽  
Marius Bill ◽  
Laura Schmalbrock ◽  
Madlen Jentzsch ◽  
Laura Kloss ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Myeloid Leukemia ◽  
Empty Vector Control ◽  
Empty Vector ◽  
The Poor ◽  
Relapse Rates ◽  
Acute Myeloid

Abstract In acute myeloid leukemia (AML) high expression of the transcription factor ERG (ETS related gene) is associated with dismal outcome. The mechanisms that regulate differential ERG expression remain to be fully elucidated. MicroRNAs (miRs), small RNAs that are able to regulate gene expression, have emerged as important players in AML. We hypothesized that part of the differential expression of ERG is mediated by miRs. In silico prediction tools identified three putative miR-9 binding sites (BS) in the 3'-untranslated region (UTR) of ERG. First, we determined the expression levels of ERG & miR-9 in eight leukemia cell lines (i.e. KG1a, K562, THP-1, MV4-11, EOL1, NB4, OCI-AML3 & ME1) & found an inverse correlation between ERG & miR-9 expression (rank correlation -0.90). The cell line KG1a had the highest ERG & low miR-9 expression, and was therefore used for miR-9 overexpression experiments. In these cells miR-9 overexpression decreased ERG expression at the mRNA level to 82±7% (P=.079) & at the protein level to 72±14% (P=.005) after 12 hours (h) compared to empty vector control transfected cells. Next, we tested the activity of the three putative miR-9 BS in the 3'-UTR of ERG using luciferase assays. 12 h after cotransfection of HEK-293T cells with a miR-9 overexpression vector & an appropriate luciferase vector containing two of the putative BS (BS1 & BS2) from the 3'-UTR of ERG, we found the luciferase activity reduced to 52±4% (P=.023). Mutation experiments showed BS1, but not BS2 to be essential for this activity. The insertion of BS3 into the luciferase vector had no effect on reporter gene expression. Thus miR-9 most likely regulates expression of the transcription factor ERG by directly binding to BS1 in its 3'-UTR. To test if a differential expression of miR-9 is also of functional significance in AML, we first analyzed its impact on cell proliferation. Overexpression of miR-9 led to decreased proliferation rates in KG1a cells compared to control vector treated cells. After 5 days, the relative cell count was 133±21% vs. 241±67% in the miR-9 overexpressing cells compared to empty vector expressing cells, respectively. Next, we determined if this difference was based on a higher apoptosis rate. An Annexin V staining revealed no significant difference between the apoptotic threshold of miR-9 overexpressing (21%) and empty vector cells (21%) after 24 h. However, a subsequent cell cycle analysis demonstrated a higher percentage of miR-9 overexpressing cells in the G2/M phase, (39±2%) compared to the empty vector control treated cells (31±3%) after 24 h (P=.084), indicating that the cell cycle is slowed or stopped during cell division. Since miR-9 targets the poor prognostic marker ERG & higher miR-9 expression led to decreased proliferation & reduced cycling in AML cells in vitro we speculated that the differential miR-9 expression would also impact the outcome of AML patients (pts). Mature miR-9 is derived from three precursor molecules of which pre-miR-9-1 & pre-miR-9-3 are known to be expressed in hematopoietic cells. We assessed the pre-miR-9-1 expression of bone marrow by real-time PCR in 131 AML pts (median age 64 [range 22 – 75] years) with favorable (n=4, 3%), intermediate (n=90, 69%), adverse (n=33, 25%), or unknown (n=4, 3%) cytogenetic risk (according to the Medical Research Council [MRC] Classification) who received a RIC-HCT. The median follow-up was 4 years. The pre-miR-9-1 expression levels were normalized to ABL to define high & low pre-miR-9-1 expressers by the median expression of all AML pts. At diagnosis, high pre-miR-9-1 expresser status associated with a lower white blood count (P=.065) and lower % of peripheral blasts (P=.108) by trend. Furthermore, pts with high pre-miR-9-1 expression were more likely to be NPM1 wild-type (P=.047) & FLT3-ITD negative (P=.020). Pts with high pre-miR-9-1 had a lower probability of relapse (P=.048). In conclusion, miR-9 targets & regulates expression of the poor outcome predictor ERG. Overexpression of miR-9 led to decreased proliferation and a pause in AML cell cycling. Furthermore, high pre-miR-9-1 expression associated with reduced relapse rates in AML. Thus a pharmacologically induced expression of miR-9 in AML blasts may improve outcomes of AML pts. Disclosures No relevant conflicts of interest to declare.

scholarly journals SIRT6 Inhibition As a Novel Approach for Treating Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5222-5222
Author(s):  
Michele Cea ◽  
Antonia Cagnetta ◽  
Debora Soncini ◽  
Paola Minetto ◽  
Davide Lovera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Allogeneic Bone ◽  
A Genome ◽  
Acute Myeloid

Abstract Currently available therapeutics against Acute Myeloid Leukemia (AML) have improved patient outcome. However, resistance develops even to novel therapies and patient overall survival remains low, especially for patients who are not eligible for allogeneic bone marrow transplantation. Therefore, there is an urgent need to overcome the biologic mechanisms underlying drug resistance in AML, to enhance the efficacy of existing treatments and to facilitate the design of novel approaches. Recently, our group has demonstrated that SIRT6, a NAD+-dependent histone deacetylase involved in genome maintenance, is frequently up-regulated in Multiple Myeloma and its targeting induces cancer cell killing (Cea M. et al, Blood 2016). Furthermore, gene expression analyses performed by our groups show that SIRT6 is also up-regulated in AML and confers poor prognosis in a series of 200 primary AML cases from our Hematology Clinic. Thus, these data suggested a role for SIRT6 in AML biology. High SIRT6 expression was typically observed in AML cell lines characterized by constitutive DNA damage and intense replicative stress. Likewise, primary AML cases exhibiting an intermediate-to-high chromosome instability (CIN) gene expression signature were also those with the highest SIRT6 expression, and worst prognosis. Subsequent studies demonstrated that SIRT6 silencing or its chemical inhibition, as observed in Multiple Myeloma exacerbates DNA damage in response to genotoxic agents, sensitizing AML cells to cytarabine (ARA-C) and idarubicin in vitro. Overall, enhancing genotoxic stress while concomitantly blocking DNA double-strand breaks (DSBs) repair response, may represent an innovative strategy to increase chemosensitivity of AML cells. Mechanistic studies revealed that SIRT6 acts as a genome guardian in AML cells by binding DNA damage sites and activating DNA-PKcs and CtIP by deacetylation, which in turn promotes DNA repair. Overall our data suggest that genomic instability is present in all hematologic malignancies including AML. Strategies aimed to shift the balance towards high DNA damage and reduced DNA repair by SIRT6 inhibition can decrease AML growth and may benefit patients with otherwise unfavorable outcomes. Disclosures Gobbi: Gilead: Honoraria; Takeda: Consultancy; Janssen: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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