Project Details
Description
Project Summary
Progenitor B cell acute lymphoblastic leukemia (B-ALL) is the most common form of cancer in children.
Although substantial progress has been made in treating children with this form of cancer, relapsed B-ALL still
accounts for the highest number of childhood deaths due to cancer. B-ALL is less common in adults but their
prognosis is much poorer (~40% survival). Thus, B-ALL remains a significant health challenge. Substantial
evidence now exists that activation of the JAK/STAT5 pathway is associated with the development of B-ALL.
Likewise, mono-allelic deletions in genes encoding a network of transcription factors required for B cell
development, including IKZF1, PAX5 and EBF1, are frequently observed in human B-ALL. We previously
established that STAT5 activation cooperates with defects in a pre-BCR pathway that ultimately impinges on a
network of transcription factors including PAX5, EBF1, PU.1, IRF4 and IKZF1 (referred to collectively hereafter
as PEPII factors) to initiate transformation. Thus, our findings demonstrated that maintaining appropriate
balance between STAT5 activation and PEPII factors is important for entraining normal B cell differentiation
and preventing B cell transformation. A key question that remains is how these two opposing transcriptional
networks function to govern B cell development and leukemia initiation. Our preliminary studies suggest that
STAT5 and PEPII bind to nearby sites within super-enhancers and recruit opposing epigenetic modifiers, such
as histone acetyltransferases (HATs) and deacetylases (HDACs). Additional preliminary ChIP-Seq data show
co-localization between STAT5 and the chromatin remodeler BRG1 at multiple enhancers. We propose that
recruitment of specific HATs, HDACS and chromatin remodelers by STAT5 and PEPII factors
sequentially alters the enhancer landscape in a manner that promotes normal B cell development.
Thus, our underlying hypothesis is that STAT5 and the PEPII transcriptional network are involved in
carefully orchestrated feedback loops to ensure both appropriate progenitor B cell expansion, and
subsequent exit from cell cycle with differentiation to the small pre-B cell stage. We further propose
that perturbations in this network lead to transformation. These hypotheses will be explored in the
following two specific aims: (1) Establish the mechanism by which STAT5 alters the enhancer landscape
during B cell development and transformation, and (2) Establish how STAT5 and PEPII factors regulate
oncogenes during B cell differentiation and transformation. Successful completion of these aims will illuminate
how two opposing transcriptional networks function to govern normal B cell development and how perturbing
that network allows for both initial progenitor B cell transformation as well as subsequent reversal of the
transformation process.
Status | Finished |
---|---|
Effective start/end date | 1/1/19 → 12/31/23 |
Funding
- National Cancer Institute: $369,126.00
- National Cancer Institute: $383,007.00
- National Cancer Institute: $338,993.00
- National Cancer Institute: $383,812.00
- National Cancer Institute: $357,826.00
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