Previous studies from our lab identified a distinct gene expression signature associated with MLL-rearranged? ALL (MLL), and identified FLT3 as a potential therapeutic target in this disease and ALL destined for relapse.? These findings have prompted a broader assessment of pathways that influence drug resistance in MLL and? ALL. As glucocorticoid resistance is associated with a poor prognosis, and has been shown to be regulated? by components of the apoptotic pathway, we propose to study the mechanisms of glucocorticoid sensitivity? and resistance in normal lymphocytes, MLL and ALL. We will interrogate gene expression signatures? associated with glucocorticoid sensitivity and resistance in MLL and ALL. Initial experiments suggest that? members of the apoptotic pathway, particularly MCL-1, are differentially expressed between blasts that are? either sensitive or resistant to glucocorticoids in vitro. We will now compare these signatures to those from? leukemias that are either sensitive or resistant to glucocorticoid treatment in vivo. As glucocorticoids are? potent modulators of gene expression, we will analyze gene expression changes that occur in sensitive and? resistant ALL samples after glucocorticoid treatment and compare these signatures to those obtained from? lymphocytes isolated from BAX/BAK double knock-out mice that eliminate any secondary signatures as they? possess a complete block to the intrinsic pathway of cell death. These studies should pinpoint, a gene? expression signature for glucocorticoid-induced apoptosis. We will characterize the role of anti-apoptotic? MCL-1 in glucocorticoid-induced apoptosis, drug resistance and leukemogenesis; and we will characterize? the pro-apoptotic BCL-2 family members BAX and BAK, and especially """"""""BH3-only"""""""" members including BIM? that participate in glucocorticoid and drug-induced apoptosis pathways. The recognition of the differences in? apoptotic pathways between the glucocorticoid sensitive and resistant populations holds the promise of? identifying targets for drug resistant leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA068484-13
Application #
7673916
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
13
Fiscal Year
2008
Total Cost
$354,060
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Lipshultz, Steven E (2018) Letter by Lipshultz Regarding Article, ""Anthracycline Cardiotoxicity: Worrisome Enough to Have You Quaking?"" Circ Res 122:e62-e63
Bansal, Neha; Barach, Paul; Amdani, Shahnawaz M et al. (2018) When is early septal myectomy in children with hypertrophic cardiomyopathy justified? Transl Pediatr 7:362-366
Mansour, Marc R; He, Shuning; Li, Zhaodong et al. (2018) JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia. J Exp Med 215:1929-1945
Temple, Jennifer L; Bernard, Christophe; Lipshultz, Steven E et al. (2017) The Safety of Ingested Caffeine: A Comprehensive Review. Front Psychiatry 8:80
Rahman, Sunniyat; Magnussen, Michael; León, Theresa E et al. (2017) Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia. Blood 129:3221-3226
Hutchins, Kelley K; Siddeek, Hani; Franco, Vivian I et al. (2017) Prevention of cardiotoxicity among survivors of childhood cancer. Br J Clin Pharmacol 83:455-465
Bona, Kira; Blonquist, Traci M; Neuberg, Donna S et al. (2016) Impact of Socioeconomic Status on Timing of Relapse and Overall Survival for Children Treated on Dana-Farber Cancer Institute ALL Consortium Protocols (2000-2010). Pediatr Blood Cancer 63:1012-8
Seftel, Matthew D; Neuberg, Donna; Zhang, Mei-Jie et al. (2016) Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission. Am J Hematol 91:322-9
Fraser, Raphael André; Lipsitz, Stuart R; Sinha, Debajyoti et al. (2016) Approximate median regression for complex survey data with skewed response. Biometrics 72:1336-1347
Lipshultz, Steven E; Anderson, Lynn M; Miller, Tracie L et al. (2016) Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors. Cancer 122:946-53

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