# Role of HOTTIP/beta-catenin-HOXA9/PRMT1 axis in hematopoietic and leukemic stem cells

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $520,285

## Abstract

Abstract:
Self-renewal is an indispensable property that allows stem cells to regenerate and maintain the homeostasis of
functionally diverse cell populations. Dergulation of self-renewal in hematopoietic stem cell (HSC) directly links
to a number of hematopoietic degenerative disorders including bone marrow failure and various blood diseases,
whereas its aberrant activation is a defining and indispensable feature of leukemia stem cells (LSCs) that sustain
the malignant phenotypes. We and others have shown that self-renewal of acute myeloid leukemia (AML) stem
cells heavily rely on the key component of canonical Wnt signaling pathway, β-catenin and the homeobox protein,
HOXA9 that are largely dispensable for adult HSCs. Although these findings reveal a contrasting functional
requirement and a potential therapeutic opportunity for AML, development of small molecule inhibitors against
oncogenic transcription factors has so far met with very little success largely due to our lack of understanding
about the molecular regulations of these proteins in mediating hematopoietic self-renewal, which has significantly
hindered progress in developing effective therapeutic strategies to treat the resultant diseases. Intriguingly, we
have recently revealed coregulation of both canonical Wnt pathway and posterior HOXA loci including HOXA9
by the long non-coding RNA (lncRNA), HOTTIP. Strikingly, we also report a novel crosstalk between β-catenin
and HOXA9 that can override their individual requirement in both mouse and human AML of HSC origins. In
search for crucial mediators for β-catenin and Hoxa9 functions, we further identified that protein arginine
methyltransferase 1 (PRMT1), which also implicates in DNA damage and repair (DDR), can functionally replace
HOXA9 or β-catenin in AML stem cell originated from HSCs. PRMT1 together with DDR complex are unbiasedly
isolated along with CTCF/cohesin complex, hematopoietic transcription factors (TFs) and nucleosome
remodeling factors as HOTTIP interacting partners by ChIRP-MS in AML cells. These findings not only discover
a novel HOTTIP/β-catenin-HOXA9/PRMT1 axis critical for mediating hematopoietic self-renewal, but also lead
to central hypothesis that HOTTIP/β-catenin-HOXA9/PRMT1 axis coordinates hematopoietic self-renewal and
characterization of the functions of individual components and their crosstalk along the axis regulates
hematopoietic specific transcription networks and DDR pathways to modulate hematopoietic self-renewal in the
disease setting. In this proposal, we will 1 decipher cooperative action of HOTTIP and hematopoietic TFs in
regulating HOXA9 and β-catenin axis; 2) dissect the molecular functions and regulation of β-catenin-
HOXA9/Prmt1 axis during normal and malignant hematopoiesis. Success completion of proposed studies not
only will establish the molecular principles, but also facilitate the design of specific therapeutics in modulating
self-renewal activities in normal and malignant stem cells, wh...

## Key facts

- **NIH application ID:** 10537540
- **Project number:** 1R01CA264932-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** So Eric
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $520,285
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537540

## Citation

> US National Institutes of Health, RePORTER application 10537540, Role of HOTTIP/beta-catenin-HOXA9/PRMT1 axis in hematopoietic and leukemic stem cells (1R01CA264932-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10537540. Licensed CC0.

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