Role of heat shock factors (Hsfs) in tumorigenesis

Project: Research project

Description

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.
StatusFinished
Effective start/end date3/1/0011/30/18

Funding

  • National Institutes of Health: $270,000.00
  • National Institutes of Health: $257,626.00
  • National Institutes of Health: $257,626.00
  • National Institutes of Health: $270,000.00
  • National Institutes of Health: $270,000.00
  • National Institutes of Health: $265,594.00
  • National Institutes of Health: $265,594.00
  • National Institutes of Health: $265,594.00

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Carcinogenesis
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Shock
Hot Temperature
Neoplasms
Organized Financing
Molecular Chaperones
Rhabdomyosarcoma
Heat-Shock Proteins
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Tumor Cell Line
Growth
Chemical Models
Tumor Suppressor Genes
Cellular Microenvironment
Tumor Microenvironment
Myoblasts
Eukaryotic Cells
Cell Differentiation
Hepatocellular Carcinoma

ASJC

  • Medicine(all)