The High mobility group a1 (Hmga1) gene enhances organoid formation, intestinal stem cell self-renewal and expands the epithelial niche cell compartment in transgenic mice by amplifying Wnt signaling.

Case ID:
C14038
Disclosure Date:
3/3/2016
Description:
UNMET NEED: High mobility group A1 (Hmga1) chromatin remodeling proteins are enriched in intestinal stem cells (ISCs), although its function in these settings had been poorly understood. Prior studies show that Hmga1 causes hyperproliferation, aberrant crypt formation, and polyposis in transgenic mice.

TECHNICAL DETAILS: Johns Hopkins researchers demonstrate that Hmga1 amplifies Wnt/β-catenin signaling to enhance self-renewal and expand the ISC compartment.  Genes encoding Wnt agonist receptors and downstream Wnt effectors. Surprisingly, Hmga1 also “builds” an ISC niche by directly up-regulating Sox9 to induce Paneth cell differentiation. This is the first example of Hmga1 fostering terminal differentiation to establish a stem cell niche. In human intestine, HMGA1 and SOX9 are highly correlated, and both become up-regulated in colorectal cancer. These results reveal a novel role for Hmga1 in intestinal homeostasis by maintaining both the stem cell pool and niche compartment and suggest that deregulated Hmga1 perturbs this equilibrium during intestinal carcinogenesis.

MAJOR RESULTS
  • Johns Hopkins researchers s reveal a novel role for Hmga1 in both stem cell self-renewal and establishment of a stem cell niche within small intestinal crypts.
  • They show for the first time that Hmga1 amplifies Wnt signaling to drive self-renewal and ISC expansion.
  • Hmga1 was found to drive increased proliferation, aberrant crypt formation, crypt fusion, and polyposis in transgenic mice by expanding the ISC compartment.
  • The researchers found a highly significant correlation between HMGA1 and SOX9 in normal human large intestinal epithelium.
  • Hmga1 “build an ISC epithelial niche” by inducing Sox9 to drives Paneth cell differentiation.
DISEASE INDICATION: Gastrointestinal Cancers

PATENT STATUS: Pending Provisional Application

ASSOCIATED PUBLICATIONS: Cancer Res 2016;76(14 Suppl):Abstract nr 1704.
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
The High mobility group a1 (Hmga1) gene enhances organoid formation, intestinal stem cell self-renewal and expands the epithelial niche cell compartment in transgenic mice by amplifying Wnt signaling. PCT: Patent Cooperation Treaty PCT PCT/US2017/022002   3/13/2017     Pending
Inventors:
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For Information, Contact:
Vera Sampels
vsampel2@jhu.edu
410-614-0300
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