Copy-number analysis identified new prognostic marker in acute myeloid leukemia

Nibourel, Olivier; Guihard, Soizic; Roumier, Christophe; Pottier, Nicolas; Terré, Christine; Paquet, Agnès; Peyrouze, Pauline; Geffroy, Sandrine; Quentin, Samuel; Alberdi, A.; Abdelali, Raouf Ben; Renneville, Aline; Demay, C; Celli-Lebras, Karine; Barbry, Pascal; Quesnel, Bruno; Castaigné, Sylvie; Dombret, Hervé; Soulier, Jean; Preudhomme, Claude; Cheok, Meyling

doi:10.1038/leu.2016.265

Cited by 37 publications

(42 citation statements)

References 39 publications

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“…Consistent with a previous report [9], this study showed that CNVs were not randomly distributed in the chromosomes. Ampli cations were more frequent in chromosomes 1,8,19, 21, and 22 of the TARGET cohort and TCGA cohorts, and deletions were more frequent in chromosomes 7, 16, and X.…”

Section: Distribution Of the Cnvsupporting

confidence: 93%

“…The array data were used on CNV analysis in previous AML studies [9,[15][16][17]. In this study, we used GWS data from TARGET to discover valuable CNV markers and validated them with the array data from TCGA.…”

Section: Discussionmentioning

confidence: 99%

“…Though the prognosis and diagnosis of AML has shifted from histological analysis to a more comprehensive analysis such as genetic alteration [8], prognosis needs to be further improved, as about 60% of intermediate risk AML patients respond to therapy variously [9], and the AML patients with rarer abnormalities need be evaluated even more properly [10]. Moreover, the role of CNV functioning as a prognosis marker by modulating gene expression in AML remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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

Niu¹,

Wu²,

Li³

et al. 2020

Preprint

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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.

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Section: Distribution Of the Cnvsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Niu¹,

Wu²,

Li³

et al. 2020

Preprint

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“…A high copy number of oncogenes has been reported in some leukemia patients. 47 The situation in the retroviral system may mimic such leukemia cases. The gene dose has some effects on the transformation efficiency.…”

Section: Discussionmentioning

confidence: 99%

Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells

et al. 2019

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The cell of origin, defined as the normal cell in which the transformation event first occurs, is poorly identified in leukemia, despite its importance in understanding of leukemogenesis and improving leukemia therapy. Although hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were used for leukemia models, whether their self-renewal and differentiation potentials influence the initiation and development of leukemia is largely unknown. In this study, the self-renewal and differentiation potentials in 2 distinct types of HSCs (HSC1 [CD150+CD41−CD34−Lineage−Sca-1+c-Kit+ cells] and HSC2 [CD150−CD41−CD34−Lineage−Sca-1+c-Kit+ cells]) and 3 distinct types of HPCs (HPC1 [CD150+CD41+CD34−Lineage−Sca-1+c-Kit+ cells], HPC2 [CD150+CD41+CD34+Lineage−Sca-1+c-Kit+ cells], and HPC3 [CD150−CD41−CD34+Lineage−Sca-1+c-Kit+ cells]) were isolated from adult mouse bone marrow, and examined by competitive repopulation assay. Then, cells from each population were retrovirally transduced to initiate MLL-AF9 acute myelogenous leukemia (AML) and the intracellular domain of NOTCH-1 T-cell acute lymphoblastic leukemia (T-ALL). AML and T-ALL similarly developed from all HSC and HPC populations, suggesting multiple cellular origins of leukemia. New leukemic stem cells (LSCs) were also identified in these AML and T-ALL models. Notably, switching between immunophenotypical immature and mature LSCs was observed, suggesting that heterogeneous LSCs play a role in the expansion and maintenance of leukemia. Based on this mouse model study, we propose that acute leukemia arises from multiple cells of origin independent of the self-renewal and differentiation potentials in hematopoietic stem and progenitor cells and is amplified by LSC switchover.

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“…Recent studies had shown that high expression of ERG and ERG amplification, the most frequent copy-number alteration (CNA), are all the worse prognostic markers in AML patients [5, 6, 33]. ETS2, one of the members of the ETS family as ERG, was previously characterized as a proto-oncogene in AMKL children that is Down-syndrome and non-Down-syndrome-related [10], but the expression and clinical prognosis of ETS2 in AML remains unknown.…”

Section: Discussionmentioning

confidence: 99%

High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions

et al. 2017

J Transl Med

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Background ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown. MethodsIn this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients.ResultsIn the first cohort, compared to low expression of ETS2 (ETS2 low), high expression of ETS2 (ETS2 high) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100). Notably, among ETS2 high patients, those received allogeneic HCT had longer OS, EFS and RFS than those with chemotherapy alone (allogeneic HCT, n = 39 vs. chemotherapy, n = 47), but treatment modules play insignificant role in the survival of ETS2 low patients (allogeneic HCT, n = 33 vs. chemotherapy, n = 53). Moreover, gene/microRNA expression data provides insights into the biological changes associated with varying ETS2 expression levels in AML. The prognostic value of ETS2 was further validated in the second AML cohort (n = 329).ConclusionsOur results indicate that ETS2 high is a poor prognostic factor in AML and may guide treatment decisions towards allogeneic HCT.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1260-2) contains supplementary material, which is available to authorized users.

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Copy-number analysis identified new prognostic marker in acute myeloid leukemia

Cited by 37 publications

References 39 publications

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

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

Mouse acute leukemia develops independent of self-renewal and differentiation potentials in hematopoietic stem and progenitor cells

High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions

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