Abstract 1351: Analysis of the in vivo tumor suppressive potential of PTPROt (truncated protein tyrosine phosphatase receptor-type O) in CLL using a transgenic mouse model
Authors: Motiwala Tasneem , Zanesi Nicola , Roy Satavisha , Mustafa Muffadal , Kutay Huban , You Jia , Frissora Frank , Lu Yuanzhi , Muthusamy Natarajan , Freitas Michael , Croce Carlo M. , Jacob Samson T. 
Published: August 2012

Abstract
Protein tyrosine phosphatases (PTPs) and kinases (PTKs) and their corresponding substrates are integrated within elaborate signal transduction networks essential for regulating several important cellular functions including growth, differentiation, cell cycle, gene transcription, the immune response and survival. Defective operation of these networks leads to aberrant tyrosine phosphorylation that contributes to the development of many human diseases including cancer. Importantly, as observed with PTKs, deregulation of PTPs plays a key role in the pathogenesis of these diseases. Thus, PTPs and their substrates represent novel molecular targets for the development of agents in the treatment of these diseases. We have previously demonstrated that the gene encoding the hematopoietic-specific truncated isoform of protein tyrosine phosphatase receptor-type O (PTPROt), a phosphatase demonstrating growth suppressor characteristics, is suppressed in chronic lymphocytic leukemia (Clin Cancer Res. 2007 Jun 1;13(11):3174-81). We have further shown that expression of PTPROt is severely impeded by T-cell leukemia 1 (TCL1), an oncoprotein aberrantly expressed in CLL B-cells (Blood. 2011 Oct 14. [Epub ahead of print]). Additionally, PTPROt plays an important role in regulating B-cell receptor (BCR) signaling (J Cell Biochem. 2010 Jul 1;110(4):846-56; Blood. 2006 Nov 15;108(10):3428-33). To comprehend the physiological relevance of PTPROt we have now generated transgenic (Tg) mice expressing PTPROt in B-cells. These mice live their normal life span and exhibit normal B- and T-cell development. Lyn and SYK kinases, the established substrates of PTPROt, are hypo-phosphorylated in B-lymphocytes from the spleen of PTPROt Tg mice relative to those from NTg mice. Because expression of PTPROt is significantly lower in splenic B-lymphocytes from TCL1 Tg mouse model of CLL relative to splenic B-cells from non-transgenic (NTg) mice (Blood. 2011 Oct 14. [Epub ahead of print]), we crossed the TCL1 Tg and PTPROt Tg mice to determine whether expression of PTPROt will inhibit/delay TCL1-mediated leukemogenesis and utilize this model to elucidate the mechanism of PTPROt function in maintaining normal cell physiology. Preliminary gene expression analysis performed on splenic B-cells from NTg, TCL1 Tg and PTPROt/TCL1 double Tg mice demonstrated that the key positive regulators of cell cycle elevated in the TCL1 Tg mice (relative to the NTg mice) are downregulated in the PTPROt/TCL1 double Tg mice (relative to the TCL1 Tg mice). Further, the spleen size as well as the total number of spleen cells was significantly lower in the PTPROt/TCL1 double Tg group relative to the TCL1 Tg group. We are currently in the process of assessing the function of the altered genes in the TCL1 Tg mouse model as well as in human CLL. [Supported by grant CA101956]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1351. doi:1538-7445.AM2012-1351