# Uncovering therapeutic vulnerabilities in AML through mechanistic interrogation of MECOM activity

> **NIH NIH K08** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $228,979

## Abstract

Project summary
Despite recent progress in the understanding of the biological underpinnings of acute myeloid leukemia (AML)
and advances in the treatment of patients with AML, fewer than one third of patients achieve a durable cure.
Therefore, deeper mechanistic insights into the drivers of AML that will lead to adjunctive, targeted therapies is
desperately needed. Recently, I elucidated a gene expression network regulated by the transcription factor
MECOM that is essential for hematopoietic stem cell maintenance and that is hijacked in high-risk AML, but the
transcriptional and epigenetic co-regulators and essential downstream effectors of the MECOM network are
unknown. In this proposal, I will test the hypothesis that MECOM directly regulates a select group of genes by
modulating critical epigenetic pathways, and a subset of those MECOM target genes is essential for AML
maintenance. I will test this through a set of two independent specific aims. I seek to 1) mechanistically define
essential co-regulators and direct targets of MECOM activity in maintaining AML progenitors, and 2) identify
indispensable downstream effectors of MECOM to uncover therapeutic vulnerabilities in AML.
I am an Instructor in Pediatric Oncology with at least 80% protected research time, seeking to apply insights from
stem cell biology to uncover and target essential pathways in AML. My career goal is to become an independent
physician-scientist studying transcriptional dysregulation in leukemia, and the purpose of this career
development award is to supplement my expertise in stem cell biology with rigorous training in in vivo modeling
of leukemia, and computational analysis. I have an outstanding mentorship team of Drs. Vijay Sankaran and
Scott Armstrong who have established track records of high impact scientific output and exemplary mentorship
of trainees, and who offer highly complementary areas of expertise. Dr. Sankaran is an innovator and leader in
modeling genetic variation in hematopoietic differentiation and stem cell maintenance, and Dr. Armstrong is an
authority on developmental gene expression programs in AML. My advisory committee and collaborators include
experts reflecting key areas of my training plan: Drs. Kim Stegmaier (AML genomics), Stu Orkin (hematopoietic
regulation), Manuel Garber (bioinformatics), Anders Hansen (chromatic biology), Seth Goldman
(transcriptomics), and Mark Minden (AML). My mentor, co-mentor, advisors, and institution are committed to my
research training, career development and progression into an independent physician-scientists at the
conclusion of this award. I will conduct this work at the world-class institutions Boston Children’s Hospital, the
Dana-Farber Cancer Institute, and the Broad Institute that will provide an environment of scientific rigor and
exceptional mentorship. With the mentored research and career development offered through this K08 award, I
will be ideally suited to establish my independent career as a phy...

## Key facts

- **NIH application ID:** 11248254
- **Project number:** 7K08CA286756-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Richard A Voit
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $228,979
- **Award type:** 7
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11248254

## Citation

> US National Institutes of Health, RePORTER application 11248254, Uncovering therapeutic vulnerabilities in AML through mechanistic interrogation of MECOM activity (7K08CA286756-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11248254. Licensed CC0.

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