Rearrangements and Amplification of <i>IER3</i> (<i>IEX-1</i>) Represent a Novel and Recurrent Molecular Abnormality in Myelodysplastic Syndromes

Steensma, David P.; Neiger, Jessemy D.; Porcher, Julie C.; Bergsagel, P. Leif; Dennis, Thomas R.; Knudson, Ryan A.; Jenkins, Robert B.; Santana-Dávila, Rafael; Kumar, Rajiv; Ketterling, Rhett P.

doi:10.1158/0008-5472.can-09-1428

Cited by 34 publications

(30 citation statements)

References 19 publications

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“…Given the significant loss of IEX-1 reported in patients with early stage MDS, 14 Figure 1A). Apparently, the decline contradicted increased cycling of the cells, as shown in Figure 1B and C, in which relatively higher proportions of KO LSK cells entered G1 and G2/S/M cycling phases than WT counterparts, concurrent with a reduced percentage of the cells at a Go or quiescent phase.…”

Section: Perturbation Of Hsc Quiescence In the Absence Of Iex-1mentioning

confidence: 93%

“…Given the significant loss of IEX-1 reported in patients with early stage MDS, 14,16 we examined the status of LSK (Lineage-Sca-1 + c-Kit + ) stem cells in IEX-1 KO mice. Loss of IEX-1 led to a significant decline in the proportion of LSK cells, in comparison with WT mice (0.10±0.07% vs. 0.24±0.06 %; P<0.01) ( Figure 1A).…”

Section: Perturbation Of Hsc Quiescence In the Absence Of Iex-1mentioning

confidence: 99%

“…12,13 Strikingly, clinical studies have shown deregulation of IEX-1 expression in approximately 60% of MDS patients. 14 It was among the most down-regulated genes in CD34 + stem cells isolated from MDS patients compared to healthy donors. 15,16 The decrease is particularly apparent in the early stage/low-risk group of MDS patients, often concomitant with excessive intramedullary apoptosis in association with hematopoietic failure.…”

Section: Introductionmentioning

confidence: 97%

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Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3)

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o ntributes significantly to MDS pathogenesis in these patients. The present study shows that null mutation of IEX-1 perturbs HSC quiescence and impairs maturation of platelets and red blood cells (RBCs). Upon BM transplantation or non-myeloablative radiation, changes resembling MDS occurred, including thrombocytopenia, a trend toward anemia, and granulocyte dysplasia. These observations underscore an indispensable role for IEX-1 in maintenance of HSC quiescence as well as in multiple differentiation steps along thrombopoiesis and erythropoiesis. IEX-1-deficient mice confer a novel model for investigating how mitochondrial dysfunction may cause MDS and how to prevent or slow down the disease. Methods MiceIEX-1 knockout (KO) mice on mixed 129Sv/C57BL/6 background were generated by gene-targeting deletion in our laboratory, as previously described. 17 The KO mice were bred with wild type (WT) C57BL/6 (B6) for 10 generations to obtain IEX-1 KO B6 mice. WT B6 mice and mice on 129Sv/B6 background were derived from breeding as above and used as controls. Cognate BL/6.SJL-Ptprc a Pep 3 /BoyJ (CD45.1) or PepJ mice were obtained from Jackson Laboratory. All experimental mice and BM donor mice were used at 6-8 weeks of age. Animals were maintained in the pathogen-free animal facilities of Massachusetts General Hospital in compliance with institutional guidelines. All animal studies were approved by the Subcommittee on Research Animal Care of the institute. Extended methods can be found in the Online Supplementary Appendix. Results Perturbation of HSC quiescence in the absence of IEX-1IEX-1 KO mice display no gross developmental defect except for modest hypertension at 2-months of age or older, 17,18 in agreement with its function required primarily in response to stress. Given the significant loss of IEX-1 reported in patients with early stage MDS, 14,16 we examined the status of LSK (Lineage-Sca-1 + c-Kit + ) stem cells in IEX-1 KO mice. Loss of IEX-1 led to a significant decline in the proportion of LSK cells, in comparison with WT mice (0.10±0.07% vs. 0.24±0.06 %; P<0.01) ( Figure 1A). Apparently, the decline contradicted increased cycling of the cells, as shown in Figure 1B and C, in which relatively higher proportions of KO LSK cells entered G1 and G2/S/M cycling phases than WT counterparts, concurrent with a reduced percentage of the cells at a Go or quiescent phase. We thus examined whether the decline was ascribed to increased apoptosis of the cells, because apoptosis in HSCs was abnormally high in many MDS patients. 19 Increased apoptosis of IEX-1 KO over WT BM cells was confirmed by apoptosis-specific terminal deoxynucleotydyl transferase-mediated dUTP nick end labeling or TUNEL (11.6±0.7% vs. 2.2±0.4%; P<0.01), which detected apoptosis at both early and late stages. Early apoptotic marker Annexin V staining further revealed that apoptosis was increased by more than 50% in the BM (6.9±0.5% vs. 4.5±0.3%; P<0.01) ( Figure 1D In spite of a reduced percentage of L...

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Section: Perturbation Of Hsc Quiescence In the Absence Of Iex-1mentioning

confidence: 93%

Section: Perturbation Of Hsc Quiescence In the Absence Of Iex-1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3)

et al. 2013

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“…Examples include TNFRSF10B, inducing apoptosis in various solid tumors, [15][16][17][18][19] PTPN13 being upregulated in pancreatic cancer and Ewing sarcoma, 20,21 or IER3 and CCR4 that have a role in myelodysplastic syndromes and lymphoma, respectively. 22,23 In addition, TP63 contributes to tumorigenesis in several cancers. 24 We conclude that a number of genes, mainly involved in immunity and apoptotic regulation, display similar expression characteristics as GTAp63 by virtue of an ERV9-LTR integrated upstream of them.…”

mentioning

confidence: 99%

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Beyer

Krönung

Leha³

et al. 2015

Cell Death Differ

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The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3' Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression.

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“…IER3 protein is rapidly and transiently induced by a variety of stimuli, including ionizing radiation, inflammatory cytokines, viral infection, anti-cancer drugs and growth factors (2,3), and is associated with apoptosis and cell proliferation (3,4). As it is involved in cell growth, IER3 expression has been examined in several human tumors, including pancreatic carcinoma, ovarian carcinoma, breast cancer, and myelodysplastic syndrome (5)(6)(7)(8). However, there has been no study of IER3 expression in human lung carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

et al. 2016

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Abstract. In order to investigate the involvement of the IER3/ PP2A-B56γ/ERK-positive feedback loop, which leads to sustained phosphorylation/activation of ERK in carcinogenesis, we immunohistochemically examined the expression of IER3 and phosphorylated ERK in lung tumor tissues. IER3 was overexpressed in all cases of adenocarcinomas examined, but was not overexpressed in squamous cell carcinomas. Phosphorylated ERK (pERK) was also overexpressed in almost all adenocarcinomas. EGFR and RAS, whose gene product is located upstream of ERK, were sequenced. Activating mutation of EGFR, which is a possible cause of overexpression of IER3 and pERK, was found only in 5 adenocarcinomas (42%). No mutation of RAS was found. We further examined the sequences of all exons of B56γ gene (PPP2R5C) and IER3, but no mutation was found. Using a single nucleotide insertion in intron 1 of PPP2R5C, which was found in the process of sequencing, allelic deletion of PPP2R5C was examined. Eight cases were informative (67%), and the deletion was found in 4 of them (50%). Three cases having deletion of PPP2R5C did not have EGFR mutation. Finally, PPP2R5C deletion or EGFR mutation that could be responsible for IER3/pERK overexpression was found in at least 8 cases (67% or more). This is the first report of a high incidence of deletion of PPP2R5C in human carcinomas. IntroductionIER3 (immediate early response gene 3) was first identified in fibroblasts from mouse in 1993 (1), and human IER3, formerly referred to as the immediate early gene X-1 (IEX-1), was first identified in human squamous cell carcinomas. The human IER3 gene is located on the short arm of chromosome 6 (6p21.3) and has 2 exons. The gene encodes 156 amino acids (2). IER3 protein is rapidly and transiently induced by a variety of stimuli, including ionizing radiation, inflammatory cytokines, viral infection, anti-cancer drugs and growth factors (2,3), and is associated with apoptosis and cell proliferation (3,4). As it is involved in cell growth, IER3 expression has been examined in several human tumors, including pancreatic carcinoma, ovarian carcinoma, breast cancer, and myelodysplastic syndrome (5-8). However, there has been no study of IER3 expression in human lung carcinoma.Protein phosphatase 2A (PP2A), which consists of structural subunit A, regulatory subunits B, and catalytic subunit C, has a broad spectrum of functions due to the variety of regulatory subunits, of which there are more than 20 kinds (9). PP2A can act as a tumor suppressor (10,11). B56 regulatory subunits are involved in cell proliferation signaling (11,12). Among them, PP2A-B56γ1 dephosphorylates Thr 202 of phosphorylated extracellular signal-regulated kinase (pERK), leading to inactivation of ERK (13). Furthermore, Garcia et al (14) found that the regulation of cell growth by IER3 is mediated by ERK, which also plays a central role in regulation of a variety of cellular events, including cell proliferation, differentiation, migration, and apoptosis (15,16). IER3 regulates ERK activity through its i...

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Rearrangements and Amplification of IER3 (IEX-1) Represent a Novel and Recurrent Molecular Abnormality in Myelodysplastic Syndromes

Cited by 34 publications

References 19 publications

Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3)

Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3)

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

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