# UBTF Tandem Duplications in Pediatric Acute Myeloid Leukemia

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $395,510

## Abstract

PROJECT SUMMARY:
Children diagnosed with acute myeloid leukemia (AML) continue to have an overall poor outcome with rates
of relapse that approach 40%. Relapsed disease is particularly resistant to conventional therapy.
Unfortunately, the molecular alterations that are common in relapsed pediatric AML have been poorly defined.
Recently our group reported on the spectrum of genetic changes in 136 children with relapsed AML and
identified tandem duplications of exon 13 of UBTF (upstream binding transcription factor) in nearly 10% of
children with relapsed AML. We further demonstrated that UBTF-tandem duplication (UBTF-TD) AMLs are
also present in 4% of children at diagnosis, yet are rare in adults, and commonly occur with FLT3-ITD and
WT1 mutations along with either normal karyotype cytogenetics or trisomy 8. Importantly, we demonstrated
that children with UBTF-TD AML have an inferior overall survival and high rates of minimal residual disease
after induction chemotherapy. Our preliminary functional studies have confirmed that UBTF-TD expression
is sufficient to drive proliferation and self-renewal of primary human hematopoietic cells and that UBTF-TD
proteins maintain canonical interactions of wild-type UBTF, but also interact with new proteins/networks
important in leukemia development, such as KMT2A and XPO1. Collectively these genomic, functional and
clinical findings suggest that UBTF-TD AMLs represents a new molecular category of pediatric AML and
establishes a strong scientific premise to investigate the molecular impact of UBTF tandem duplications in
primary hematopoietic cells. We hypothesize that UBTF-TD represents in new initiating lesion that drives the
expression of specific transcriptional networks, in particular the HOXB program, through new interactions with
the genome and from collaboration with unique cooperating mutations and interacting proteins. We will test
our hypothesis with the following specific aims using a combination of genetic tools in human and mouse
hematopoietic cells. Specific Aim 1: Decipher the molecular mechanisms of UBTF-TD in leukemogenesis;
Specific Aim 2: Dissect the contribution of UBTF-TD and co-occurring mutations to leukemogenesis using in
vivo models; Specific Aim 3. Establish the contribution of UBTF domains and interacting proteins to UBTF-
TD mediated transformation. Not only will the proposed studies elucidate the transcriptional and epigenetic
impact of UBTF-TD expression in primary hematopoietic cells, including patient samples, but they will also
establish multiple mouse and human model systems for this new subtype of high-risk pediatric AML and
evaluate potential vulnerabilities. The successful completion of these proposed studies, and the resulting
model systems, will ultimately be used to develop therapeutic approaches to target UBTF-TD AMLs and most
importantly to improve the long-term outcome of children with these leukemias.

## Key facts

- **NIH application ID:** 10933513
- **Project number:** 5R01CA276079-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Jeffery M Klco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,510
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933513

## Citation

> US National Institutes of Health, RePORTER application 10933513, UBTF Tandem Duplications in Pediatric Acute Myeloid Leukemia (5R01CA276079-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10933513. Licensed CC0.

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