# Role of MED12L- Associated Chromatin Enhancers in Pediatric Acute Megakaryoblastic Leukemia

> **NIH NIH P20** · ARKANSAS CHILDREN'S HOSPITAL RES INST · 2022 · $269,500

## Abstract

Summary
 The fusion of CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3, also known as ETO2) and
GLIS family zinc finger 2 (GLIS2) proteins is the most recurrent (30%) alternation in pediatric de novo acute
megakaryoblastic leukemia (AMKL). For infants and young children (<3 years of age) harboring ETO2-GLIS2,
outcomes are among the worst of all pediatric acute myeloid leukemia (AML) subtypes, with poor responses to
induction therapy, high incidence of relapse (~90%), and dismal 5-year survival rates (<20%). Genome
sequencing studies have shown the ETO2-GLIS2 fusion and epigenetic regulation to be key drivers of the
disease. For instance, transcriptional deregulation in this AML subtype was linked to the cooperative binding of
ETO2-GLIS2 to H3K27ac (histone H3, acetyl-lysine amino acid position 27) enriched super-enhancer (SE)
chromatin. In leukemic blasts, ETO2-GLIS2 induces formation of unique leukemia-specific SE (neo-SE)
elements that would be distantly located from their canonical binding sites in normal megakaryocyte (MK)
progenitors. While ETO2-GLIS2 fusion is considered to impact leukemic properties by imbalance of ERG-GATA1
transcription factors (TFs) and enhancer activity in a single oncogenic “hit”, detailed mechanisms by which the
fusion protein rearranges chromatin architecture to deregulate transcriptional programs remain elusive.
 Mediator (MED) proteins are known to assemble transcriptional coactivators distal to the RNA polymerase II
binding site to regulate gene expression. Specifically, in leukemic cells, the MED12 subunit or its MK-lineage
paralog MED12L of the MED-kinase module was reported to co-recruit regulatory transcription factors (e.g.,
bromodomain 4, ERG, p300, GATA2) at H3K27ac-enriched SE elements. Moreover, somatic mutations of
MED12L or amplifications of chr3q, which harbors the gene, also have been reported as novel oncogenic drivers
in squamous cell carcinoma and prostate cancer respectively. MED12L is found overexpressed and controlled
by the ETO2-GLIS2 bound SE in this AML subtype. Understanding the role of MED12L in enhancer mechanisms
could provide insight into novel treatment approaches.
 Based on rigorous preliminary studies, we hypothesize that ETO2-GLIS2 exploits focal chromatin features
to develop oncogenic neo-SEs, favoring leukemic growth, and that MED12L potentiates formation and
transcriptional linkage of these neo-SE elements to induce leukemic gene expression. We will test our hypothesis
by pursuing the following specific aims: (1) Determine how ETO2-GLIS2 alters chromatin architecture to facilitate
leukemia-specific transcriptional programs and (2) Determine the degree to which MED12L contributes to the
global chromatin remodeling and formation of neo-SE.

## Key facts

- **NIH application ID:** 10496404
- **Project number:** 2P20GM121293-06
- **Recipient organization:** ARKANSAS CHILDREN'S HOSPITAL RES INST
- **Principal Investigator:** Samrat Roy Choudhury
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $269,500
- **Award type:** 2
- **Project period:** 2017-07-11 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496404

## Citation

> US National Institutes of Health, RePORTER application 10496404, Role of MED12L- Associated Chromatin Enhancers in Pediatric Acute Megakaryoblastic Leukemia (2P20GM121293-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10496404. Licensed CC0.

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