Kofler Reinhard, Univ.-Prof. Dr.med.univ.

University / Clinic: Medical University Innsbruck
Institute: Division of Molecular Pathology
 
Research Area: Molecular Oncology

Email: Reinhard.Kofler@i-med.ac.at
Web: dmp.i-med.ac.at/index.php/en/


Research Topic:
Glucocorticoid (GC) hormones and their derivatives range among the most frequently prescribed therapeutic drugs worldwide. They are used to fight infections and unwanted immune responses such as those seen in autoimmune diseases. Moreover, GC induce programmed cell death (apoptosis) in certain cells of the lymphoid lineage and, hence, are used as essential components in treating lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). Our lab is interested in the molecular basis of the therapeutic GC effects in cells of the immune system with particular emphasis on their anti-leukemic properties. Most, if not all, GC effects are mediated via their cognate receptor (GR, NR3C1). Upon ligand binding the GR translocates into the nucleus where it changes the expression of a host of genes. These gene regulations are supposed to mediate many of the effects of GC, but which gene accounts for what physiologic and/or therapeutic effect is poorly understood. To better understand this clinically and biologically important transcriptional response, we exploit a number of microarray-based technologies and corresponding bioinformatics tools including whole genome expression profiling, microRNA screening, transcription factor binding site detection, alternative transcript identification and translatome analyses in numerous biological systems including children with ALL, cell line models and (genetically modified) mice. Many of the wet lab techniques for sample preparation as well as the bioinformatics tools can be used for "deep sequencing" technologies which are currently being included in our portfolio. These techniques then provide "candidate genes" for certain effects. The functional significance of the identified gene regulations is then assessed using lentiviral systems for conditional and/or constitutive gene over-expression and knock-down by RNA interference in T- and preB-cell leukemia models and other experimental systems. Newly discovered GC regulated genes may lead to new druggable targets, once they have been verified and their function determined. Thus, our work helps understanding the response of lymphoid cells to GCs and might provide concepts for a more efficient therapy of ALL.

Project:
  Bioinformatic gene expression analysis in childhood acute lymphoblastic leukemia (ChALL)
details ...

Selected publications:
 
  Etemad Ahari S, Obermair G, Bindreither D, Benedetti A, Stanika R, Di Biase V, Burtscher V, Koschak A, Kofler R, Geley S, Wille A, Lusser A, Flockerzi V, Flucher B
Differential neuronal targeting of a new and two known calcium channel β4 subunit splice variants correlates with their regulation of gene expression.
J Neurosci. 2014 Jan 22;34(4):1446-61

  Bindreither D, Ecker S, Gschirr B, Kofler A, Kofler R, Rainer J
The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells.
BMC Genomics. 2014 Aug 7;15:662.

  Aneichyk T, Bindreither D, Mantinger C, Grazio D, Goetsch K, Kofler R, Rainer J
Translational profiling in childhood acute lymphoblastic leukemia: no evidence for glucocorticoid regulation of mRNA translation.
BMC Genomics. 2013 Dec 1;14:844.

  Kullmann M, Grubbauer C, Goetsch K, Jäkel H, Podmirseg S, Trockenbacher A, Ploner C, Cato A, Weiss C, Kofler R, Hengst L
The p27-Skp2 axis mediates glucocorticoid-induced cell cycle arrest in T-lymphoma cells.
Cell Cycle 12 (16): 2625 - 2635.

  Rainer J, Lelong J, Bindreither D, Mantinger C, Ploner C, Geley S, Kofler R
Research resource: transcriptional response to glucocorticoids in childhood acute lymphoblastic leukemia.
Mol Endocrinol. 2012 Jan;26(1):178-93.

  Eberhart K, Rainer J, Bindreither D, Ritter I, Gnaiger E, Kofler R, Öfner P, Renner K
Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia.
Biochim Biophys Acta. 2011 Jun;1807(6):719-25.

  Oppl B, Kofler A, Schwarz S, Rainer J, Kofler R
Establishing a sensitive and specific assay for determination of glucocorticoid bioactivity
Wien.Klin.Wochenschr. 123:222-229.

  Mansha M, Carlet M, Ploner C, Gruber G, Wasim M, Wiegers G, Rainer J, Geley S, Kofler R
Functional analyses of Src-like adaptor (SLA), a glucocorticoid-regulated gene in acute lymphoblastic leukemia.
Leuk Res. 2010 Apr;34(4):529-34. Epub 2009 Jul 29.

  Prokudin I, Stasyk T, Rainer J, Bonn G, Kofler R, Huber L
Comprehensive proteomic and transcriptomic
characterization of hepatic expression signatures affected in p14 liver conditional knockout mice
Proteomics. 2011 Feb;11(3):469-80. doi: 10.1002/pmic.201000400. Epub 2011 Jan 11

  Carlet M, Janjetovic K, Rainer J, Schmidt S, Panzer-Grümayer R, Mann G, Prelog M, Meister B, Ploner C, Kofler R
Expression, regulation and function of phosphofructo-kinase/fructose-biphosphatases (PFKFBs) in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia cells.
BMC Cancer. 2010 Nov 23;10:638.

  Gruber G, Carlet M, Turtscher E, Meister B, Irving J, Ploner C, Kofler R
Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis.
Leukemia 23:820-823.

  Rainer J, Ploner C, Jesacher S, Ploner A, Eduardoff M, Mansha M, Wasim M, Panzer-Grümayer R, Trajanoski Z, Niederegger H, Kofler R
Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia.
Leukemia. 2009 Apr;23(4):746-52. Epub 2009 Jan 15.

  Ploner C, Rainer J, Lobenwein S, Geley S, Kofler R
Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells.
Apoptosis. 2009 Jun;14(6):821-8.

  Ploner C, Rainer J, Lobenwein, Geley S, Kofler R
Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells.
Apoptosis 14:821-828.

  Rainer J, Ploner C, Jesacher S, Ploner A, Eduardoff M, Mansha M, Wasim M, Panzer-Grümayer R, Trajanoski Z, Niederegger H, Kofler R
Glucocorticoid regulated microRNAs and mirtrons in acute lymphoblastic leukemia.
Leukemia 23:746-752.

  Rainer J, Ploner C, Jesacher S, Ploner A, Eduardoff M, Mansha M, Wasim M, Panzer-Grümayer R, Trajanoski Z, Niederegger H, Kofler R
Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia.
Leukemia. 2009 Apr;23(4):746-52.

  Ploner C, Rainer J, Lobenwein S, Geley S, Kofler R
Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells.
Apoptosis. 2009 Jun;14(6):821-8.

  Ploner C, Rainer J, Niederegger H, Eduardoff M, Villunger A, Geley S, Kofler R.
The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia.
Leukemia. 2008 Feb;22(2):370-7. Epub 2007 Nov 29.

  Ploner C, Kofler R, Villunger A. (2008)
Noxa: at the tip of the balance between life and death.
Oncogene. 2008 Dec;27 Suppl 1:S84-92.

  Ploner C, Rainer J, Niederegger H, Eduardoff M, Villunger A, Geley S, Kofler R
The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia.
Leukemia 22:370-377.

  Ploner C, Kofler R, Villunger A
Noxa: at the tip of the balance between live and death.
Oncogene 27 Suppl 1:S84-S92.

  Ploner C, Rainer J, Niederegger H, Eduardoff M, Villunger A, Geley S, Kofler R
The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia.
Leukemia. 2008 Feb;22(2): 370-7.

  Presul E, Schmidt S, Kofler R, Helmberg A
Identification, tissue specific expression and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor.
J. Mol. Endocrinol. 38:79-90.

  Schmidt S, Rainer J, Riml S, Ploner C, Jesacher S, Achmüller C, Presul E, Skvortsov S, Crazzolara R, Fiegl M, Raivio T, Jänne O, Geley S, Meister B, Kofler R
Identification of glucocorticoid response genes in children with acute lymphoblastic leukemia.
Blood. 2006; Mar 1; 107(5): 2061-9

  Schmidt S, Rainer J, Riml S, Ploner C, Jesacher S, Achmüller C, Presul E, Skvortsov S, Crazzolara R, Fiegl M, Raivio T, Jänne O, Geley S, Meister B, Kofler R
Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.
Blood. 2006 Mar 1;107(5):2061-9. Epub 2005 Nov 17.

  Ausserlechner M, Obexer P, Deutschmann A, Geiger K, Kofler R
A retroviral expression system based on tetracycline-regulated tricistronic transactivator/repressor vectors for functional analyses of antiproliferative and toxic genes.
Mol. Cancer Ther. 5:1927-1934.

  Schmidt S, Rainer J, Riml S, Ploner C, Jesacher S, Achmüller C, Presul E, Skvortsov S, Crazzolara R, Fiegl M, Raivio T, Jänne O, Geley S, Meister B, Kofler R
Identification of glucocorticoid response genes in children with acute lymphoblastic leukemia.
Blood 107:2061-2069.

  Schmidt S., Irving J, Minto L, Matheson E, Nicholson L, Ploner A, Parson W, Kofler A, Amort M, Erdel M, Hall A, Kofler R
Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor.
FASEB J. 20:2600-2602.

  Schmidt S, Rainer J, Riml S, Ploner C, Jesacher S, Achmüller C, Presul E, Skvortsov S, Crazzolara R, Fiegl M, Raivio T, Janne O A, Geley S, Meister B, Kofler R
Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.
Blood. 2006 107(5):2061-2069.

  Ploner C, Schmidt S, Presul E, Renner K, Schröcksnadel K, Rainer J, Riml S, Kofler R
Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia.
J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):153-60. Epub 2005 Jan 26.

  Ausserlechner M, Obexer P, Geley S, Kofler R
G1 arrest by P16INK4A uncouples growth from cell cycle progression in leukemia cells with deregulated cyclin E and c-myc expression.
Leukemia 19:1051-1057.

  Parson W, Kirchebner R, Mühlmann R, Renner K, Kofler A, Schmidt S, Kofler R
Cancer cell line identification by short tandem repeat profiling: power and limitations.
FASEB J. 19:434-436.

  Ploner C, Schmidt S, Presul E, Renner K, Schröcksnadel K, Rainer J, Riml S, Kofler R
Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia.
J. Steroid Biochem. Mol. Biol. 93:153-160.

  Ploner C, Schmidt S, Presul E, Renner K, Schröcksnadel K, Rainer J, Riml S, Kofler R
Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia.
J Steroid Biochem Mol Biol. 93(2-5):153-160.

  Riml S, Schmidt S, Ausserlechner M, Geley S, Kofler R
Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells.
Cell Death Differ. 2004 Jul;11 Suppl 1:S65-72.

  Schmidt S, Rainer J, Ploner C, Presul E, Riml S, Kofler R
Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance.
Cell Death Differ. 2004 Jul;11 Suppl 1:S45-55.

  Ausserlechner M, Obexer P, Böck G, Geley S, Kofler R
Cyclin D3 and c-myc control glucocorticoid-induced cell cycle arrest but not apoptosis in lymphoblastic leukemia cells.
Cell Death Differ. 11:165-174.

  Riml S, Schmidt S, Ausserlechner M, Geley S, Kofler R
Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells.
Cell Death Differ. 11 Suppl 1:S65-S72.

  Schmidt S, Rainer J, Ploner C, Presul E, Riml S, Kofler R
Glucocorticoid-induced apoptosis and glucocorticoid resistance: Molecular mechanisms and clinical relevance.
Cell Death Differ. 11 Suppl 1:S45-S55.

  Schmidt S, Rainer J, Ploner C, Presul E, Riml S, Kofler R
Glucocorticoid-induced apoptosis and glucocorticoid resistance: Molecular mechanisms and clinical relevance.
Cell Death Differ. 11 Suppl 1:S45-S55.

  Tonko-Geymayer S, Goupille O, Tonko M, Soratroi C, Yoshimura A, Streuli C, Ziemiecki A, Kofler R, Doppler W
Regulation and function of the cytokine-inducible SH-2 domain proteins, CIS and SOCS3, in mammary epithelial cells.
Mol Endocrinol, 16, 1680-1695