T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid disorder that results from an over proliferation of immature lymphocytes in the blood and bone marrow. It has been determined that 60% of patients stricken with T-ALL aberrantly express TAL-1 and have been shown to respond poorly to chemotherapy. This research sought to determine if TAL-1 influences the expression of the Bcl-2 family members Bcl-2 (anti-apoptotic), Bad and Bax (pro-apoptotic). TAL-1 and Bcl-2 levels were elevated while Bad and Bax levels were lower in etoposide-treated Jurkat cells as compared to TRAIL-treated and dual-treated Jurkat cells in which TAL-1 and Bcl-2 levels were lower while Bad and Bax levels were elevated. These results suggest TAL-1 up-regulates Bcl-2 and suppress Bad and Bax expression in response to etoposide treatment, thus inducing an anti-apoptotic response in the cell. These results also suggest that TRAIL and the dual treatment of etoposide and TRAIL down-regulates TAL-1 and Bcl-2 expression while up-regulating Bad and Bax, thus inducing a pro-apoptotic response in the cell. / Department of Biology

Tal-1 is a transcription factor that is frequently ectopically expressed in the majority of cases of T-cell acute lymphoblastic leukemia (T-ALL). The ectopic expression of Tal-1 in patients with ALL has been found to decrease susceptibility to chemotherapeutic drugs and apoptosis. Thus, this study focuses on the effects of endogenously expressed Tal-1 in the Jurkat cell line on three Bcl-2 family members (Bcl-2, Bcl-xL, and Bid) and the inhibition of apoptosis and cell viability when exposed to apoptosis inducing drugs such as etoposide. The data obtained indicate that when treated with etoposide for 12 h Jurkat cells endogenously expressing Tal-1 have an 81% higher level of anti-apoptotic Bcl-2 expression, an 18% lower level of anti-apoptotic Bcl-xL, expression, and a 31% lower level of pro-apoptotic Bid expression compared to Jurkat cells lacking Tal-1 expression. The data also demonstrates that Jurkat cells endogenously expressing Tal-1 have a 15.94% lower amount of cell death after treatment with etoposide for 12 h and a 20.34% lower amount of cell death after treatment with etoposide for 24 h when compared to Jurkat cells that lack Tal-1 expression. Thus, the endogenous expression of Tal-1 increases the amount of the anti-apoptotic Bcl-2 expression and decreases the amount of the pro-apoptotic Bid creating an overall anti-apoptotic signal within the cell. / Department of Biology

Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Several proto-oncogenes that encode nuclear proteins are activated by various chromosomal translocations in ALL including TALI, TAL2, and LMO1 and LMO2. Ectopic TALI expression is observed in about 50 % of T-ALL and is the most common genetic anomaly associated with this pathology. Of interest to the present work is the characterization of various multiprotein complexes and protein protein interactions that drive T-ALL progression (as it relates to TALI and LMO1) and over expression of TALI and LMO1 has been shown to have inhibitory effects on apoptosis. Recent data suggests possible interactions between these two oncoproteins and the protein product of the lipoprotein lipase (LPL) gene. Lipoprotein lipase has a complex pattern of regulation and can be regulated in different ways including down-regulation upon induction of TNF-a in 3T3-L1 cells. Thus, this study was undertaken to determine if LPL is expressed in cells over expressing TAL1 and LMO1. Results from this study demonstrated an increase in LPL expression at both transcriptional and translational level in cells engineered to express TAL1 alone and TAL1 and LMO1 together. This finding is a step forward to understanding mechanisms that result in apoptosis prevention in T-ALL. Therefore, the apoptosis preventive role seen in cells that over express TAL and LMO1 and the presence of LPL in the same cell line, theorizes an apoptosis preventive role for lipoprotein lipase as well. / Department of Physiology and Health Science

Currently, the intensive chemotherapy remains the first line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although these regimens have significantly improved patient outcomes, their use is associated with debilitating morbidities and fatal relapses, highlighting the great need in new agents that target essential survival signals in leukemia. Thus, the overall goal of my project was to gain insights into the signaling abnormalities that regulate aberrant proliferation and survival of B-ALL cells in an effort to identify novel targets in this malignancy. This study demonstrated that pre-B cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) activity was required for the survival and proliferation of a p53-/-PrkdcSCID/SCID mouse model of B-ALL. I extended this discovery to human disease, demonstrating that SYK was activated in primary B-ALL, independent of the pre-BCR expression. The small molecule SYK inhibitor fostamatinib (fosta) significantly attenuated proliferation of 79 primary diagnostic B-ALL samples at clinically achievable concentrations. Importantly, fosta treatment reduced dissemination of engrafting B-ALL cells into the spleen, liver, kidney and central nervous system (CNS) in a NOD.Prkdcscid/scidIl2rgtm1Wjl/SzJ xenotransplant model of B-ALL. Analysis of signaling abnormalities using a high-throughput phospho-flow cytometry platform demonstrated that pediatric and adult B-ALL samples exhibit variable basal activation of BCR, iii PI3K/AKT/mTOR, MAPK and JAK/STAT pathways. Importantly, we identified that fosta-mediated inhibition of SYK, PLC2, CRKL and EIF4E phosphorylation in B-ALL was predictive of its anti-leukemic activity, and was distinct from the cellular actions of other small molecule inhibitors of key nodal signaling pathways. Examination of molecular mechanism of fosta action by gene expression profiling revealed transcriptional effects of fosta treatment that included, most notably, potent inhibition of pathways involved in lymphocyte activation and inflammation. In conclusion, this study demonstrates that SYK signaling is crucial for B-ALL survival and provides detailed characterization of cellular and molecular mechanisms of fosta action in B-ALL. These data argue in favor of testing small molecule SYK inhibitors in pediatric and adult B-ALL.

Thesis (Ph.D) --Murdoch University, 2004. / Thesis submitted to the Division of Health Sciences. Includes bibliographical references (leaves 328-352).

Thesis (Ph.D.)--University of Western Australia, 2007.

Thesis (M.S.)--University of British Columbia, 2005. / Includes bibliographical references (leaves 33-41). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M. Sc.)--University of British Columbia, 2005. / Includes bibliographical references (leaves 33-41).

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23101号 / 医博第4728号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 松田 文彦, 教授 藤田 恭之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction The problem at hand is understanding if pediatric acute lymphoblastic leukemia (ALL) treatment affects neurocognitive function or development. As the children battle ALL and are given treatments such as cranial radiation therapy and chemotherapy, they are having issues later on in life because the treatment regimens are very strong and are given during a crucial period of development. Purpose Statement and Question Does one pediatric treatment option affect neurocognitive development more than another later in life? Literature Review Research was conducted online via Google Scholar and East Tennessee State University Library database. Key terms used were pediatric ALL and neurocognitive effects of chemotherapy and radiation. Five studies were collected all pertaining to the question at hand. Findings The findings from the research collected was that certain demographics have a stronger effect on the development of a child post-ALL treatment. The treatment regimen and the strength of the treatment affect cognitive development. Cognitive impairment related to attention occurs with all children treated for ALL. Conclusion Nurses see first-hand the effects treatment have on children as the grow. We have to provide resources to help with attention deficits among other cognitive issues that result from treatment. The literature gave a great insight to what effects are to be expected post-treatment.