Dataset Information

Homeobox protein HB9 binds to the prostaglandin E receptor 2 promoter and inhibits intracellular cAMP mobilization in leukemic cells.

ABSTRACT:

Background

HB9 is highly expressed in translocation t(7;12) positive infant AML.

Results

HB9 binds to the PTGER2 promoter, down-regulates PTGER2 gene expression and subsequently represses cAMP synthesis in hematopoietic cells.

Conclusion

Expression of HLXB9 represses PTGER2 mediated signaling.

Significance

First molecular report of HB9-dependent target gene regulation in hematopoietic cells. The transcription factor HB9, encoded by the homeobox gene B9 (HLXB9), is involved in the development of pancreatic beta- and motor neuronal cells. In addition, HLXB9 is recurrently rearranged in young children with acute myeloid leukemia characterized by a chromosomal translocation t(7;12)-HLXB9/TEL and concomitant high expression of the unrearranged, wild-type HLXB9 allele. However, target genes of HB9 in hematopoietic cells are not known to date. In this study, we used ChIP-on-chip analysis together with expression profiling and identified PTGER2 (prostaglandin E receptor 2) as a target gene of HB9 in a hematopoietic cell line. The functional HB9 homeodomain as well as the HB9 binding domain within the PTGER2 promoter are essential for binding of HB9 to the PTGER2 promoter region and down-regulation of PTGER2 expression. Functionally, HB9 conducted down-regulation of PTGER2 results in a reduced content of intracellular cAMP mobilization and furthermore the decreased PTGER2 gene expression is valid in bone marrow cells from translocation t(7;12) positive patients. Among the primary and secondary target genes of HB9 in the myeloid cell line HL60, 78% of significantly regulated genes are down-regulated, indicating an overall repressive function of HB9. Differentially regulated genes were preferentially confined to pathways involved in cell-adhesion and cell-cell interactions, similar to the gene expression footprint of HLXB9-expressing cells from t(7;12) positive patients.

SUBMITTER: Wildenhain S

PROVIDER: S-EPMC3504783 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Homeobox protein HB9 binds to the prostaglandin E receptor 2 promoter and inhibits intracellular cAMP mobilization in leukemic cells.

Wildenhain Sarah S Ingenhag Deborah D Ruckert Christian C Degistirici Özer Ö Dugas Martin M Meisel Roland R Hauer Julia J Borkhardt Arndt A

The Journal of biological chemistry 20121008 48

<h4>Background</h4>HB9 is highly expressed in translocation t(7;12) positive infant AML.<h4>Results</h4>HB9 binds to the PTGER2 promoter, down-regulates PTGER2 gene expression and subsequently represses cAMP synthesis in hematopoietic cells.<h4>Conclusion</h4>Expression of HLXB9 represses PTGER2 mediated signaling.<h4>Significance</h4>First molecular report of HB9-dependent target gene regulation in hematopoietic cells. The transcription factor HB9, encoded by the homeobox gene B9 (HLXB9), is in ...[more]

PMID: 23048027

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Project description:Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, ?(12)-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of ?(12)-PGJ3. The stability of ?(12)-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of ?(12)-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. ?(12)-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. ?(12)-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that ?(12)-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while ?(12)-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared ?(12)-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of ?(12)-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. ?(12)-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest ?(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.

Dataset Information

Homeobox protein HB9 binds to the prostaglandin E receptor 2 promoter and inhibits intracellular cAMP mobilization in leukemic cells.

Background

Results

Conclusion

Significance

Publications

Homeobox protein HB9 binds to the prostaglandin E receptor 2 promoter and inhibits intracellular cAMP mobilization in leukemic cells.

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