Acute lymphoblastic leukemia (T-ALL) originates from the T cell lineage. The disease represents 15% of pediatrics and 25% of adult ALL cases annually, making it the most common cancer in the very young and elderly populations. Disease relapse occurs frequently, and more than 80% of the relapse T-ALL cases harbor the TP53 mutation. These patients develop resistance to chemotherapy that is associated with very poor prognosis. Furthermore, those patients who do go into remission are faced with severe complications due to their prior aggressive chemotherapy. It is therefore critical to understand the molecular mechanisms that cause and drive T-ALL in order to discover novel therapeutic targets with better specificity and reduced toxicity. Patients with primary and relapse T-ALLs as well as mice with radiation- induced T-ALL have a very high incidence of activated Notch1 and the TP53 mutation. Indeed, TP53-deficient mice exhibit a 70% incidence of ALLs, suggesting that this is a good model for investigating the biology and molecular mechanisms of T-ALL. We have found that deletion of heat shock factors (Hsfs) Hsf4, Hsf2, or Hsf1 in TP53-deficient mice leads to significant protection against development of T-ALL. These data suggest that therapeutic inhibition of Hsfs could be a key to eliminating T-ALL. In this grant, we have designed studies to test the efficacy of hsf deletion in mouse models of T-ALL and track the genome-wide shift in transcription from bone marrow (BM) hemopoietic stem cells (HSCs) to thymic progenitors to mature T cells. Finally, we will examine whether reducing Hsf expression levels in human T-ALL cell lines and primary tumor cells in vitro or inducible deletion of Hsfs in T-ALL-bearing mice will be a good therapeutic option for T-ALLs. We hypothesize that Hsfs are not essential for T cell development;however, they cooperate with oncogenes and tumor suppressor genes to control T-ALL development, and depletion of Hsfs result in the inability of T-ALL cells to survive.
Aim 1 will determine the efficacy of Hsf deletion in mouse models of T-ALL using ionizing radiation (IR)- or mutant Pten-, induced T-ALLs.
In Aim 2 we will determine the molecular mechanisms underlying Hsf deletion in mouse models of T-ALL and will assess global transcriptional changes during T cell development in the presence or absence of hsfs and TP53 genes using RNA sequencing. Exome sequencing of HSCs following IR that will reveal profile mutations that are eliminated when Hsfs are deleted.
In Aim 3 we will assess if the depletion of Hsfs from human or mouse primary tumors or T-ALL cell lines leads to tumor cell death.

Public Health Relevance

Acute lymphoblastic leukemia (T-ALL) originates from the T cell lineage. The disease represents 15% of pediatrics and 25% of adult ALL cases annually making it the most common cancer in the very young and elderly population. Disease relapse occurs frequently and more than 80% of the relapse T-ALL cases harbor TP53 mutation and these patients develop resistance to chemotherapy that is associated with very poor prognosis. We have found that deletion of heat shock transcription factor (Hsf) in TP53-deficient mice leads to complete protection against development of T-ALL. These data suggest that therapeutic inhibition of Hsf could be a key to eliminating T-ALL. In this grant, will test the efficacy of hsf deletion in mouse models of T-ALL and we will examine if reducing Hsf levels in human T-ALL cell lines in vitro, or deletion of Hsfs from human T-ALL- bearing mice in vivo will be a good therapeutic option for T-ALLs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA132640-13A1
Application #
8632076
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Mccarthy, Susan A
Project Start
2000-03-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
13
Fiscal Year
2014
Total Cost
$262,884
Indirect Cost
$87,628
Name
Georgia Regents University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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