# Role of Asxl1 in normal hematopoiesis and pathogenesis of myeloid malignancies

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $365,750

## Abstract

Additional sex comb-like (ASXL) genes are human homologues of Drosophila-Asx gene which encode
important regulators of gene expression. ASXL1 mutations occur at high frequencies in multiple forms of
myeloid malignancy patients with poor prognosis. ASXL1 mutations are mostly nonsense/frameshift, causing
truncation of the protein lacking the C-terminal PHD finger, which is detectable in patient samples with ASXL1
mutations. We have recently shown that transgenic expression of an ASXL1 truncation in mice (Asxl1Y588XTg)
results in increased HSC/HPC pools and pathogenesis of myeloid malignancies (Blood 2017). BAP1 is
activated by ASXL1 to deubiquitinate H2AK119 during polycomb protein-mediated gene repression. BAP1
mutations also occur in patients with MDS. Despite the significant impact of ASXL1 truncation mutations on the
pathogenesis of myeloid malignancies, the underlying mechanisms remain largely unknown, hindering the
development of effective targeted therapeutics. Our proteomics studies discovered that ASXL1aa1-587 exhibits
an increased binding affinity to BAP1 compared to ASXL1FL and gains an interaction with BRD4, a member of
the BET family. BRD4 is involved in multiple biologic processes, including transcription, DNA replication,
epigenetic regulation, and tumorigenesis. We hypothesize that truncated ASXL1 dysregulates HSC/HPCs and
causes myeloid malignancies through altering the function of the BAP1 deubiquitinase complex and gaining
interaction with BRD4. Challenging this critical question has great translational impact and is the major goal of
this application. In Aim 1, we will use our recently generated Tet-on/off Asxl1Y588XTg mice to assess in prove-
of-concept whether silencing transgene expression by withdrawing doxycycline can eradicate the ASXL1aa1-587-
mediated abnormal hematopoietic phenotype and myeloid malignancies. We will apply bPPI-seq, a novel
sensitive assay to confirm/identify the true ASXL1aa1-587 interactors at physiological conditions in vivo. In Aim 2,
we will determine the role of BRD4-ASXL1aa1-587 interaction in truncated ASXL1-mediated HSC/HPC
dysregulation and myeloid malignancy development. We will examine whether BRD4 inhibitor (EP11313)
treatment is capable of preventing and/or rescuing the abnormal hematopoietic phenotype and myeloid
malignancies in Asxl1Y588XTg mice. In Aim 3, we will determine the role of BAP1 in truncated ASXL1-mediated
abnormal HSC/HPC behavior and pathogenesis of myeloid malignancies in vivo. We will decipher how
ASXL1aa1-587 alters the function of BAP1 in HSC/HPCs in vivo. The effects of ASXL1aa1-587 on genome-wide
BAP1 and H2AK119Ub occupancy in LK cells will be determined by ChIP-seq and correlated with the gene
expression data. These studies are timely and fundamentally important for advancing our knowledge on
ASXL1 truncation mutation-mediated HSC/HPC dysregulation and myeloid malignancy development. The
success of this project will likely identify novel therapeutic targets in the ga...

## Key facts

- **NIH application ID:** 10115504
- **Project number:** 7R01CA172408-07
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Mingjiang Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,750
- **Award type:** 7
- **Project period:** 2014-01-02 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115504

## Citation

> US National Institutes of Health, RePORTER application 10115504, Role of Asxl1 in normal hematopoiesis and pathogenesis of myeloid malignancies (7R01CA172408-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115504. Licensed CC0.

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