Up-regulation of Survivin by the E2A-HLF Chimera Is Indispensable for the Survival of t(17;19)-positive Leukemia Cells

Okuya, Mayuko; Kurosawa, Hidemitsu; Kikuchi, Jiro; Furukawa, Yusuke; Matsui, Hirotaka; Aki, Daisuke; Matsunaga, Takayuki; Inukai, Takeshi; Goto, Hiroaki; Altura, Rachel A.; Arisaka, Osamu; Look, A. Thomas; Inaba, Toshiya

doi:10.1074/jbc.m109.023762

Cited by 15 publications

(8 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our series, BIRC5 gene was amplified only in 1 sample but a gene copy number gain was present in 35% of investigated tumors; moreover, FISH results correlated with mRNA levels and protein expression, thus indicating that in pediatric MPNST BIRC5 gene copy number is likely involved in protein overexpression. Alternatively, overexpression of survivin might depend on regulation at the transcriptional level, as already reported in other malignancies [37] ; in this case, NF1 loss of function might promote survivin transcription by activation of nuclear factor-κb (NF-κB) via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway or TCF-4/b-catenin pathway [38] .…”

Section: Discussionmentioning

confidence: 87%

Survivin Expression and Prognostic Significance in Pediatric Malignant Peripheral Nerve Sheath Tumors (MPNST)

et al. 2013

View full text Add to dashboard Cite

Malignant peripheral nerve sheath tumors (MPNST) are very aggressive malignancies comprising approximately 5–10% of all soft tissue sarcomas. In this study, we focused on pediatric MPNST arising in the first 2 decades of life, as they represent one the most frequent non-rhabdomyosarcomatous soft tissue sarcomas in children. In MPNST, several genetic alterations affect the chromosomal region 17q encompassing the BIRC5/SURVIVIN gene. As cancer-specific expression of survivin has been found to be an effective marker for cancer detection and outcome prediction, we analyzed survivin expression in 35 tumor samples derived from young patients affected by sporadic and neurofibromatosis type 1-associated MPNST. Survivin mRNA and protein expression were assessed by Real-Time PCR and immunohistochemical staining, respectively, while gene amplification was analyzed by FISH. Data were correlated with the clinicopathological characteristics of patients. Survivin mRNA was overexpressed in pediatric MPNST and associated to a copy number gain of BIRC5; furthermore, increased levels of transcripts correlated with a higher FNCLCC tumor grade (grade 1 and 2 vs. 3, p = 0.0067), and with a lower survival probability (Log-rank test, p = 0.0038). Overall, these data support the concept that survivin can be regarded as a useful prognostic marker for pediatric MPNST and a promising target for therapeutic interventions.

show abstract

Section: Discussionmentioning

confidence: 87%

Survivin Expression and Prognostic Significance in Pediatric Malignant Peripheral Nerve Sheath Tumors (MPNST)

et al. 2013

View full text Add to dashboard Cite

show abstract

“…It has been postulated that E2A-HLF oncogenic properties might be due to the dual effects of E2A loss of function in conjunction with induction of target genes by the fusion protein [ 18 ]. Therefore, we investigated in sorted B-cell progenitors from transgenic mice the expression of known E2A-HLF target genes including Nfil3 [ 35 ], Slug [ 36 ], Lmo2 [ 37 , 38 ], Bcl2 [ 38 , 39 ], Birc5 [ 40 ], cell death receptor Dr5 [ 41 ] and Zfp521 [ 21 ]. Increased expression levels were only detected for Birc5 (p-value<0.05) and Lmo2 (p-value< 0.01) in E2A-HLF-expressing versus wild type B-cell progenitors ( S6 Fig ).…”

Section: Discussionmentioning

confidence: 99%

Conditional Expression of E2A-HLF Induces B-Cell Precursor Death and Myeloproliferative-Like Disease in Knock-In Mice

2015

View full text Add to dashboard Cite

Chromosomal translocations are driver mutations of human cancers, particularly leukemias. They define disease subtypes and are used as prognostic markers, for minimal residual disease monitoring and therapeutic targets. Due to their low incidence, several translocations and their biological consequences remain poorly characterized. To address this, we engineered mouse strains that conditionally express E2A-HLF, a fusion oncogene from the translocation t(17;19) associated with 1% of pediatric B-cell precursor ALL. Conditional oncogene activation and expression were directed to the B-cell compartment by the Cre driver promoters CD19 or Mb1 (Igα, CD79a), or to the hematopoietic stem cell compartment by the Mx1 promoter. E2A-HLF expression in B-cell progenitors induced hyposplenia and lymphopenia, whereas expression in hematopoietic stem/progenitor cells was embryonic lethal. Increased cell death was detected in E2A-HLF expressing cells, suggesting the need for cooperating genetic events that suppress cell death for B-cell oncogenic transformation. E2A-HLF/Mb1.Cre aged mice developed a fatal myeloproliferative-like disorder with low frequency characterized by leukocytosis, anemia, hepatosplenomegaly and organ-infiltration by mature myelocytes. In conclusion, we have developed conditional E2A-HLF knock-in mice, which provide an experimental platform to study cooperating genetic events and further elucidate translational biology in cross-species comparative studies.

show abstract

“…AIF is a flavoprotein that is normally confined to the mitochondrial intermembrane space, but induces chromatin condensation and fragmentation of DNA into high molecular weight forms of >50 kb when it translocates to the nucleus (28,29). Interestingly, down-regulation of survivin induces the translocation of AIF in various cancer cell lines (30)(31)(32).…”

Section: Molecular Functions Of Survivinmentioning

confidence: 99%

Investigations of survivin: the past, present and future

Cheung¹

2011

Front Biosci

View full text Add to dashboard Cite

Survivin is a member of the inhibitors-of-apoptosis protein (IAPs) family. It promotes cell survival through interference with multiple cell cycle-related proteins such as INCENP and Aurora B kinase. Survivin also inhibits cell death through interference with both caspase-dependent and -independent cell apoptosis. Interestingly, recent evidence suggests that survivin may also play a role in the regulation of cancer cell autophagy. At the clinical level, studies on clinical specimens have shown that survivin expression is up-regulated in various human cancers and its up-regulation is associated with tumour resistance to both chemotherapy and radiation therapy. On the basis of these findings, survivin has been proposed as an attractive target for new anti-cancer interventions. However, despite the role that survivin plays in cancer cell survival and anti-drug response, the development of survivin inhibitors is relatively slow as compared to other therapeutic inhibitors for cancer treatment. In this review, the relationships between survivin expression and the causation of drug resistance in cancers are re-addressed. This review also summarizes the recent development of survivin inhibitors for clinical usage.

show abstract

Up-regulation of Survivin by the E2A-HLF Chimera Is Indispensable for the Survival of t(17;19)-positive Leukemia Cells

Abstract: The E2A-HLF fusion transcription factor generated by t(17;19)(q22;p13) translocation is found in a small subset of pro-B cell acute lymphoblastic leukemias (ALLs) and promotes leukemogenesis by substituting for the antiapoptotic function of cytokines.

Cited by 15 publications

References 40 publications

Survivin Expression and Prognostic Significance in Pediatric Malignant Peripheral Nerve Sheath Tumors (MPNST)

Survivin Expression and Prognostic Significance in Pediatric Malignant Peripheral Nerve Sheath Tumors (MPNST)

Conditional Expression of E2A-HLF Induces B-Cell Precursor Death and Myeloproliferative-Like Disease in Knock-In Mice

Investigations of survivin: the past, present and future

Contact Info

Product

Resources

About