# Role of lincRNAs in HSC function and leukemogenesis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $532,517

## Abstract

Abstract
Hox genes, especially HOXA and HOXB genes, are critical for maintaining the balance between self-renewal
and differentiation of hematopoietic stem cells (HSCs). Dysregulation of HOXA and/or HOXB genes is a
dominant mechanism of leukemic transformation. Aberrant HOX gene expression is associated with fusion
genes involving MLL1 and NUP98, and mutations in NPM1 and CEBPA. However, the epigenetic mechanisms
that regulate HOX gene transcription to control HSC function remain to be explored. Furthermore, it is critical to
elucidate how HOX genes are aberrantly activated during leukemogenesis. Better understanding of these
critical questions will assist in the development of highly effective and selective targeted therapies. We recently
identified a HoxB locus associated long intergenic noncoding RNA (lncRNA), HoxBlinc, which controls
hematopoietic lineage commitment and differentiation by organizing CTCF mediated active chromatin domain
to facilitate anterior HoxB gene activation. HoxBlinc recruits the Setd1a/MLL1 complexes to activate HoxB
genes. We found that HoxBlinc lncRNA is overexpressed in significant portions of AML patients, and AML
patients with high HoxBlinc expression had significantly shortened survival compare to patients with low
HOCBLINC expression. Furthermore, transgenic expression of HoxBlinc in mice leads to increased pools of
LT-HSCs and ST-HSCs, and development of lethal AML-like disease. We hypothesize that HoxBlinc lncRNA is
a critical epigenetic regulator of HSCs, by controlling the activation of Hox and other key HSC-regulating genes
through modulation of chromatin dynamics. In addition, up-regulation of HoxBlinc may represent a potent
oncogenic event in leukemogenesis. To test these hypothesis, we will: 1) determine the role of HoxBlinc
lncRNA in HSC biology and behavior by performing serial transplantation and paired daughter cell assays
using purified HoxBlinc-Tg HSCs; 2) determine whether transgenic HoxBlinc expression is sufficient to perturb
hematopoiesis and cause myeloid malignancies in mice; 3) investigate the mechanism(s) by which HoxBlinc
lncRNA regulates behaviors of different stages of HSCs by examining global changes in HoxBlinc chromatin
binding, 3D chromatin organization, histone modifications, chromatin accessibility, as well as transcription
profiles in HSCs purified from WT and HoxBlinc-Tg mice; 4) examine if the function exerted by HoxBlinc
lncRNA in HSCs is dependent on the Setd1a/MLL1 complexes; 5) explore whether HOXBLINC lncRNA can
serve as an effective therapeutic target for AMLs by examining whether HoxBlinc loss is capable of mitigating
NPM1C+- or other mutation-driven myeloid malignancies via abrogating the signature aberrant HOX gene
expression. Success of the proposed studies will result in fundamental knowledge regarding the regulation of
HSCs by lncRNAs. Our studies could establish HoxBlinc as a powerful oncogenic lncRNAs during
leukemogenesis. HOXBLINC lncRNA might represent a novel t...

## Key facts

- **NIH application ID:** 10312758
- **Project number:** 5R01HL141950-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Suming Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $532,517
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312758

## Citation

> US National Institutes of Health, RePORTER application 10312758, Role of lincRNAs in HSC function and leukemogenesis (5R01HL141950-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10312758. Licensed CC0.

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