nih-gov/researchfestival.nih.gov/2016/posters/understanding-role-runx1-tle1-interaction-pathogenesis-familial-platelet
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<title>Understanding the role of RUNX1-TLE1 interaction in the pathogenesis of familial platelet disorder with associated myeloid malignancy | NIH Research Festival</title>
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<article><div class="banner banner--blue banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2016.jpg');--banner-background-focus: 100% 0%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2016-09-14">September 14</time> <time datetime="2016-09-16">16, 2016</time></strong></p></div></div></div></div></article>
<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>Understanding the role of RUNX1-TLE1 interaction in the pathogenesis of familial platelet disorder with associated myeloid malignancy</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2016-09-14">Wednesday, September 14, 2016</time>
Poster Session I
</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">3:00 4:30 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NHGRI</strong></p></div><div class="schedule__description"><p><strong>GEN-12</strong></p></div></div></div></div><h2>Authors</h2><ul><li>HI Alkadi</li><li>Y Gao</li><li>TS Karpova</li><li>L Garret</li><li>S Wincovitch</li><li>A Sorrell</li><li>DA Ball</li><li>JJ Greene</li><li>L Cheng</li><li>PP Liu</li></ul><h2>Abstract</h2><p>Familial platelet disorder with associated myeloid malignancy (FPDMM), also known as familial platelet disorder/acute myeloid leukemia (FPD/AML), is characterized with defective megakaryopoiesis and propensity for leukemia (~60% of patients). FPDMM is caused by inherited heterozygous mutations in RUNX1, which encodes a transcription factor. An FPDMM family was identified carrying a novel GC insertion in RUNX1, leading to a frameshift mutation (L472fsX). This caused a disruption of the VWRPY domain; a conserved binding site for the repressor protein TLE1. My research is aimed to unravel how the actions of these proteins contribute to the development of FPDMM, which represents a novel mechanism in FPDMM pathogenesis. To evaluate the physical and functional interaction between RUNX1 (L742fsX) and TLE1, I performed forster resonance energy transfer (FRET), and transactivation assay of RUNX1s target promoter. When YFP-TLE1 was co-transfected with CFP-RUNX1-wt, it gave a FRET efficiency of 10% ± 3.3%. When YFP-TLE1 was co-transfected with CFP-RUNX1 (L472fsX), the FRET efficiency was only 0.65% ± 1.8%, indicating no binding between RUNX1 (L742fsX) and TLE1. Moreover, TLE1 repressed RUNX1-wt activity when co-transfected with its co-factor CBFβ. On the other hand, TLE1 did not repress RUNX1 (L472fsX) activity. These findings demonstrate that the L472fsX mutation disrupts RUNX1-TLE1 interaction and RUNX1-repression by TLE1. To further understand the role of RUNX1-TLE1 interaction in FPDMM pathogenesis, I will characterize megakaryopoiesis and use RNA-seq to profile gene expression in two models: induced pluripotent stem cells (iPS) derived from the patients cells, and Runx1 mutant mice generated with CRISPR-Cas9.</p><p><strong>Scientific Focus Area</strong>: Genetics and Genomics</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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