# Biology and Targeting of noncoding RNAs in AML

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $356,850

## Abstract

The prognosis of acute myeloid leukemia (AML) is still very poor. Thus, understanding the mechanisms
regulating the biology of AML is important for developing effective therapies for this disease. Non-random
chromosomal abnormalities are identified in 50-55% of all AML patients. In contrast, about 45-50% of all AML
cases are cytogenetically normal (CN-AML). Recent work has identified novel recurrent gene mutations in CN-
AML. Among them, mutations of the nucleophosmin (NPM1) gene, represent the most common genetic
alteration in CN-AML. Recently a novel class of noncoding RNAs (transcripts longer than 200 nucleotides)
named long noncoding RNAs (lncRNAs) was discovered. While lncRNAs contribute to carcinogenesis in solid
tumors, their role in AML has not been characterized. Our group recently identified the lncRNA HOXB-AS3
among the top up-regulated lncRNAs in NPM1 mutated (NPM1mut) CN-AML cases. We further showed that
HOXB-AS3 knockdown leads to a decrease blast proliferation and colony formation in AML cell lines and
primary AML patients in vitro. Silencing HOXB-AS3 in vivo using locked nucleic acid (LNA) gapmers resulted in
an increased survival of treated patient derived xenograft (PDX) mice with respect to controls. Comparative
proteomics identified several RNA binding protein partners of HOXB-AS3, such as EBP1, which are associated
with ribosomal biogenesis. Further experiments indicated that HOXB-AS3 binds to EBP1 and regulates
ribosomal biogenesis in AML by affecting the interactions between EBP1 and NPM1 complex. Altogether, our
preliminary data supports our hypothesis that HOXB-AS3 plays an important role in NPM1mut AML, and
blocking HOXB-AS3 may be a viable therapeutic target in NPM1mut AML. The overall goal of this is proposal
is to dissect the mechanisms through which HOXB-AS3 contributes to myeloid leukemogenesis and to explore
how to target therapeutically this lncRNA. We will accomplish this goal through the following Specific Aims
(SA): 1) Specific Aim 1: To elucidate the mechanisms by which HOXB-AS3 promotes leukemogenesis
in AML. We will perform in vitro and in vivo studies to elucidate how HOXB-AS3 modulates cell proliferation
and ribosome biogenesis; 2) Specific Aim 2: To investigate in vivo the pharmacokinetic
(PK), pharmacodynamics (PD) and anti-leukemic activity of a synthetic nanoparticle tagged LNA
gapmer against HOXB-AS3 using PDX models of AML. In this aim we will conduct preclinical studies of
synthetic Tf-NP LNA gapmer against HOXB-AS3 in PDX models of AML overexpressing HOXB-AS3 to
evaluate: a) toxicity; b) plasma PK and intracellular concentrations; c) PD endpoints; d) PK/PD modeling; and
e) efficacy At completion of this project, we will have an increased understanding of the role of lncRNAs in
NPM1mut AML and incorporated these findings into future treatment strategies that may improve overall
outcomes.

## Key facts

- **NIH application ID:** 10129919
- **Project number:** 5R01CA240612-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Ramiro Garzon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129919

## Citation

> US National Institutes of Health, RePORTER application 10129919, Biology and Targeting of noncoding RNAs in AML (5R01CA240612-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129919. Licensed CC0.

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