Interleukin-2 receptor alpha-chain (CD25) expression on leukaemic blasts is predictive for outcome and level of residual disease in AML

2009 ◽  
Vol 45 (9) ◽  
pp. 1692-1699 ◽  
Author(s):  
Monique Terwijn ◽  
Nicole Feller ◽  
Anna van Rhenen ◽  
Angèle Kelder ◽  
Guus Westra ◽  
...  
Keyword(s):  
Residual Disease ◽  
Interleukin 2 ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Cd25 Expression ◽  
Interleukin 2 Receptor ◽  
Receptor Alpha Chain

scholarly journals Interleukin-2 Receptor Alpha Chain, Also Called CD25, Is a Potential Target in Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Giovanna Carrà ◽  
Antonio Cartellà ◽  
Beatrice Maffeo ◽  
Paola Circosta ◽  
Alessandro Cignetti ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Cd25 Expression ◽  
Interleukin 2 Receptor ◽  
Cycle Arrest ◽  
Receptor Alpha Chain

Background: Acute lymphoblastic leukemia (ALL) is a molecularly heterogeneous disease originating from clonal proliferation of precursor B-lineage cells. In adults, ALL diagnosis is still associated with a dismal prognosis due to the lack of specific targeted therapies. This study was designed to investigate the expression of interleukin-2 receptor alpha chain CD25 in B-ALL and its biological significance, especially following the availability of specific CD25 targeting compounds. Methods:The expression of IL2RA (CD25 gene) was detected by flow cytometry (FC), immunohistochemistry and Western blot analysis, in 25 newly diagnosed ALL patients, both Philadelphia positive (12 patients) and Philadelphia negative (13 patients). Similarly, CD25 expression was assessed in four B-ALL commercially available cell lines. Infection with shRNA specifically directed against CD25 was used to evaluate apoptosis induction and cell cycle arrest in primary B-ALL cells established from two patients. Results:Our data suggest that ALL, and in particular Ph-positive ALL, aberrantly expresses the interleukin-2 receptor alpha chain, CD25. Whereas normal B cells display low amounts of CD25, primary ALL cells and ALL cell lines (over)-express CD25. While the high frequency of CD25 on the surface of many different hematological tumor cells has been established and confirmed in our study, there is little investigation focusing on the significance of CD25 expression. Indeed, CD25 may be present on ALL cells and enable oncogenic signaling pathways. In such respect, we observed that CD25 silencing in primary cells promotes cell cycle arrest and apoptosis induction. While these data support the rational to target CD25, ALL cells did not appear to be in-vitro sensitive to basiliximab, an antibody able to target the Il2RA, but in-vivo investigations are needed to better assess the effects of this therapeutic approach in ALL context. Conclusions:We concluded that CD25 expression is elevated in patients with B-ALL. Our results also demonstrate that CD25 silencing induces cell cycle arrest and apoptosis. The latter result has important implications from a therapeutic point of view. Targeting CD25 receptor with anti-CD25 antibodies or peptide mimetics could be an effective strategy for targeting leukemic cells. Additionally, high CD25 expression could be exploited for the development of CAR-T therapy Disclosures Saglio: Roche:Research Funding;Pfizer:Research Funding;Incyte:Research Funding;Novartis:Research Funding;Ariad:Research Funding;Bristol-Myers Squibb:Research Funding.

scholarly journals Delineation of an enhancerlike positive regulatory element in the interleukin-2 receptor alpha-chain gene.

1990 ◽  
Vol 10 (2) ◽  
pp. 850-853 ◽  
Author(s):  
B B Lin ◽  
S L Cross ◽  
N F Halden ◽  
D G Roman ◽  
M B Toledano ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Interleukin 2 ◽  
Chain Gene ◽  
Enhancer Activity ◽  
Enhancer Element ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Interleukin 2 Receptor ◽  
Positive Regulatory Element ◽  
Receptor Alpha Chain

We have delineated a positive regulatory element in the interleukin-2 receptor alpha-chain gene (IL-2R alpha) between positions -299 and -243 that can potently activate a heterologous (herpesvirus thymidine kinase [tk]) promoter in phorbol myristate acetate (PMA)-induced Jurkat T cells and is functional when cloned in either orientation. This enhancerlike element contains a site (-268/-257) that can bind NF-kappa B; however, unlike the immunoglobulin kappa gene kappa B enhancer element, the IL-2R alpha kappa B-like site alone can only weakly activate a heterologous promoter. Adjacent 5' and 3' sequences also weakly activate the tk-CAT vector, but constructs combining the IL-2R alpha kappa B-like site plus adjacent 5' and 3' sequences potently activate gene expression. This combination of regions is essential for potent PMA-induced transcription from the tk promoter. Experiments using constructs in which IL-2R alpha upstream sequences are sequentially deleted suggested that there is a region 5' of position -299 which can suppress IL-2R alpha promoter and/or enhancer activity. Thus, it is possible that both positive and negative elements may be important in the regulation of IL-2R alpha gene transcription.

scholarly journals Kappa B site-dependent activation of the interleukin-2 receptor alpha-chain gene promoter by human c-Rel.

1992 ◽  
Vol 12 (9) ◽  
pp. 4067-4075 ◽  
Author(s):  
T H Tan ◽  
G P Huang ◽  
A Sica ◽  
P Ghosh ◽  
H A Young ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Interleukin 2 ◽  
Regulatory Elements ◽  
Chain Gene ◽  
Nf Kappa B ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Interleukin 2 Receptor ◽  
Alpha Gene ◽  
Receptor Alpha Chain

The cis-acting control elements of the interleukin-2 receptor alpha-chain (IL-2R alpha) gene contain a potent kappa B-like enhancer whose activity can be induced by various mitogenic stimuli. Recent cloning of the p50 and p65 subunits of the kappa B-binding protein NF-kappa B complex revealed a striking sequence homology of these proteins with the c-rel proto-oncogene product (c-Rel). On the basis of this homology, we examined the potential role of c-Rel in controlling IL-2R alpha transcription. We now demonstrate that the recombinant human c-Rel protein binds to the kappa B element in the IL-2R alpha promoter and results in alteration of the DNA structure in the adjacent downstream regulatory elements containing the CArG box and the GC box. We found that human c-Rel can activate transcription from the IL-2R alpha promoter, but not the kappa B-containing human immunodeficiency virus type 1 promoter, upon cotransfection into Jurkat T cells. Furthermore, truncation of the carboxyl terminus of c-Rel results in a c-Rel mutant (RelNA) that (i) localizes exclusively in the nucleus and (ii) acts in synergy with wild-type c-Rel in activating transcription from the kappa B site of the IL-2R alpha promoter. Finally, induction of surface IL-2R alpha expression coincides with the induced levels of endogenous c-Rel and induced c-Rel binding to the IL-2R alpha kappa B site. Our study identified c-Rel as one component of the Rel/NF-kappa B-family proteins involved in the kappa B-dependent activation of IL-2R alpha gene expression. Furthermore, our results suggest that a Re1NA-like cellular factor (e.g., NF-kappa B p50 or p49 subunit) acts in synergy with c-Re1 during T-cell activation.

scholarly journals HTLV-1 p27rex stabilizes human interleukin-2 receptor alpha chain mRNA.

1990 ◽  
Vol 9 (12) ◽  
pp. 4161-4166 ◽  
Author(s):  
H. Kanamori ◽  
N. Suzuki ◽  
H. Siomi ◽  
T. Nosaka ◽  
A. Sato ◽  
...  
Keyword(s):  
Interleukin 2 ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Interleukin 2 Receptor ◽  
Receptor Alpha Chain

Delineation of an enhancerlike positive regulatory element in the interleukin-2 receptor alpha-chain gene

1990 ◽  
Vol 10 (2) ◽  
pp. 850-853
Author(s):  
B B Lin ◽  
S L Cross ◽  
N F Halden ◽  
D G Roman ◽  
M B Toledano ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Interleukin 2 ◽  
Chain Gene ◽  
Enhancer Activity ◽  
Enhancer Element ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Interleukin 2 Receptor ◽  
Positive Regulatory Element ◽  
Receptor Alpha Chain

We have delineated a positive regulatory element in the interleukin-2 receptor alpha-chain gene (IL-2R alpha) between positions -299 and -243 that can potently activate a heterologous (herpesvirus thymidine kinase [tk]) promoter in phorbol myristate acetate (PMA)-induced Jurkat T cells and is functional when cloned in either orientation. This enhancerlike element contains a site (-268/-257) that can bind NF-kappa B; however, unlike the immunoglobulin kappa gene kappa B enhancer element, the IL-2R alpha kappa B-like site alone can only weakly activate a heterologous promoter. Adjacent 5' and 3' sequences also weakly activate the tk-CAT vector, but constructs combining the IL-2R alpha kappa B-like site plus adjacent 5' and 3' sequences potently activate gene expression. This combination of regions is essential for potent PMA-induced transcription from the tk promoter. Experiments using constructs in which IL-2R alpha upstream sequences are sequentially deleted suggested that there is a region 5' of position -299 which can suppress IL-2R alpha promoter and/or enhancer activity. Thus, it is possible that both positive and negative elements may be important in the regulation of IL-2R alpha gene transcription.

Kappa B site-dependent activation of the interleukin-2 receptor alpha-chain gene promoter by human c-Rel

1992 ◽  
Vol 12 (9) ◽  
pp. 4067-4075
Author(s):  
T H Tan ◽  
G P Huang ◽  
A Sica ◽  
P Ghosh ◽  
H A Young ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Interleukin 2 ◽  
Regulatory Elements ◽  
Chain Gene ◽  
Nf Kappa B ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Interleukin 2 Receptor ◽  
Alpha Gene ◽  
Receptor Alpha Chain

The cis-acting control elements of the interleukin-2 receptor alpha-chain (IL-2R alpha) gene contain a potent kappa B-like enhancer whose activity can be induced by various mitogenic stimuli. Recent cloning of the p50 and p65 subunits of the kappa B-binding protein NF-kappa B complex revealed a striking sequence homology of these proteins with the c-rel proto-oncogene product (c-Rel). On the basis of this homology, we examined the potential role of c-Rel in controlling IL-2R alpha transcription. We now demonstrate that the recombinant human c-Rel protein binds to the kappa B element in the IL-2R alpha promoter and results in alteration of the DNA structure in the adjacent downstream regulatory elements containing the CArG box and the GC box. We found that human c-Rel can activate transcription from the IL-2R alpha promoter, but not the kappa B-containing human immunodeficiency virus type 1 promoter, upon cotransfection into Jurkat T cells. Furthermore, truncation of the carboxyl terminus of c-Rel results in a c-Rel mutant (RelNA) that (i) localizes exclusively in the nucleus and (ii) acts in synergy with wild-type c-Rel in activating transcription from the kappa B site of the IL-2R alpha promoter. Finally, induction of surface IL-2R alpha expression coincides with the induced levels of endogenous c-Rel and induced c-Rel binding to the IL-2R alpha kappa B site. Our study identified c-Rel as one component of the Rel/NF-kappa B-family proteins involved in the kappa B-dependent activation of IL-2R alpha gene expression. Furthermore, our results suggest that a Re1NA-like cellular factor (e.g., NF-kappa B p50 or p49 subunit) acts in synergy with c-Re1 during T-cell activation.

Interaction between NF-kappa B- and serum response factor-binding elements activates an interleukin-2 receptor alpha-chain enhancer specifically in T lymphocytes

1993 ◽  
Vol 13 (4) ◽  
pp. 2536-2545
Author(s):  
A A Kuang ◽  
K D Novak ◽  
S M Kang ◽  
K Bruhn ◽  
M J Lenardo
Keyword(s):  
T Cells ◽  
Serum Response Factor ◽  
Interleukin 2 ◽  
Response Factor ◽  
Nf Kappa B ◽  
Receptor Alpha ◽  
Alpha Chain ◽  
Interleukin 2 Receptor ◽  
Serum Response ◽  
Receptor Alpha Chain

We find that a short enhancer element containing the NF-kappa B binding site from the interleukin-2 receptor alpha-chain gene (IL-2R alpha) is preferentially activated in T cells. The IL-2R alpha enhancer binds NF-kappa B poorly and is only weakly activated by the NF-kappa B site alone. Serum response factor (SRF) binds to a site adjacent to the NF-kappa B site in the IL-2R enhancer, and both sites together have strong transcriptional activity specifically in T cells. Surprisingly, the levels of SRF constitutively expressed in T cells are consistently higher than in other cell types. Overexpression of SRF in B cells causes the IL-2R enhancer to function as well as it does in T cells, suggesting that the high level of SRF binding in T cells is functionally important.

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