The phenotype of cancer cells that present in patients often reflects an immature state and is caused by altered gene expression profiles. I hypothesize that resting, differentiated cells actively maintain specific gene expression profiles and, as such, prevent de-differentiation towards an immature phenotype with altered growth properties. We have previously identified a constitutive signal in resting lymphocytes that dictates gene expression signatures. This signal is generated by an equilibrium between positive and negative regulators, follows a T cell receptor (TCR)-like signaling pathway, and results in basal activity of Erk and Abl kinases. The involvement of Abl kinases may have consequences for CML patients who are receiving STI-571 therapy. In this proposal and in my future line of research, I strive to understand how continuous signal-input in lymphocytes, in vivo, preserves specific gene expression profiles in differentiated cells and, in doing so, prevents unwanted de-differentiation and development of cancer. I propose the following specific aims:
Aims 1, 2: Through the use of innovative mouse models, I will determine the effects of inducible removal of the TCR signaling molecules ZAP-70 and LAT (alone or combined with g-radiation) on constitutive gene expression profiles and maintenance of a differentiated T cell phenotype. Biochemical-, gene expression profiling-, and phenotypical parameters will be determined and correlated.
Aim 3 : To gain a better understanding of controlled gene expression in human peripheral T lymphocytes, and thus its relevance to human disease, I will compare the constitutive signals and gene expression programs in ex vivo T lymphocytes from mice and humans upon pharmacological inhibition, e.g. STI-571, or RNAi targeting of key signaling molecules and link the results to Aims 1, 2.
Aim 4 :I will determine the mechanism of Abl function in T cells by studying its the contribution to constitutive signaling and maintenance of gene expression profiles, which is relevant to CML patients who receive STI-571 (an Abl inhibitor) therapy. These studies will lead to a better understanding of the mechanism of, and the need for, preservation of specific gene expression profiles, thus preventing unwanted de-differentiation and development of T cell malignancies. Resolving these issues will be an important contribution to the understanding of cancer development and may have implications for cancer therapy and prevention.
| Limnander, Andre; Zikherman, Julie; Lau, Tannia et al. (2014) Protein kinase C? promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance. Mol Cell Biol 34:1474-85 |
| Markegard, Evan; Trager, Evan; Yang, Chih-wen Ou et al. (2011) Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCR? gene expression. PLoS One 6:e25540 |
| Chakraborty, Arup K; Das, Jayajit; Zikherman, Julie et al. (2009) Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes. Sci Signal 2:pt2 |
| Das, Jayajit; Ho, Mary; Zikherman, Julie et al. (2009) Digital signaling and hysteresis characterize ras activation in lymphoid cells. Cell 136:337-51 |
