# Deciphering inv3/t(3;3) Myeloid Leukemia Vulnerabilities via Proteogenomics and N-terminal Proteomics

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $44,731

## Abstract

PROJECT SUMMARY
The overall objective of this proposal is to develop and apply novel proteogenomic approaches to identify
therapeutic vulnerabilities of chromosome 3 rearranged myeloid leukemias. Chromosome 3 inversions or
transversions (inv3/t(3;3)) leukemias result in aberrant overexpression of oncogenic transcription factor MECOM
(MDS1 and EVI1 complex locus, specifically a truncated isoform EVI1) and decreased expression of tumor
suppressor GATA2. Inv3/t(3;3) abnormal myeloid leukemia patients have no targeted precision therapies as they
are resistant to standard of care regimens like Tyrosine Kinase Inhibitors (TKIs), and so experience dismal 5-
year survival rates of <5%. Consequently, there is an unmet need for new approaches to therapeutically target
inv3/t(3;3)-driven leukemias. Canonically, MECOM is critical in regulating hematopoiesis, however, alternative
transcripts of MECOM drive oncogenesis when overexpressed as a result of chromosomal rearrangements. In
addition to oncogenic MECOM, I hypothesize that the inv3/t(3;3) abnormality leads to the production of additional
leukemia specific proteoforms that contribute to the aggressive nature of this disease. Here, I will test this
hypothesis by comparing inv3/t(3;3) positive and negative myeloid leukemia cell lines with healthy cord-blood
derived hematopoietic progenitor cells using novel proteogenomic approaches. To test this hypothesis I will:
identify inv3/t(3;3) specific genes by combining RNA-Seq and bulk proteomics (Aim 1), utilize PacBio long read
sequencing with proteomics to identify novel protein coding alternative transcripts (Aim 2) and capture inv3/t(3;3)
unique post-translational processes through utilization of my N-terminal proteomics methodology termed N-
SPyCE (neo-N-terminal SP3 Pyridine Carboxaldehyde Enrichment) (Aim 3). In exciting preliminary data, I have
already identified several key candidates for MECOM-affected genes, including HLA-DPB1, IL16, SPP1, CD74
and ALDH1A1. Pathway analysis of my bulk proteomic data revealed a striking correlation between inv3/t(3;3)
harboring cells and increased cathepsin-mediated protease activity. I hypothesize that there are specific
cathepsin cleaved substrates that are specific effectors of inv3/t(3;3) biology. Overall, this project proposes to
utilize proteogenomics to detect disease specific transcript isoforms, to validate their expression at the protein
level and to investigate leukemia specific proteoforms as therapeutically relevant.

## Key facts

- **NIH application ID:** 10997848
- **Project number:** 1F31CA295026-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Alexandra Chloe Turmon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,731
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997848

## Citation

> US National Institutes of Health, RePORTER application 10997848, Deciphering inv3/t(3;3) Myeloid Leukemia Vulnerabilities via Proteogenomics and N-terminal Proteomics (1F31CA295026-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997848. Licensed CC0.

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