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

Award Number: F31CA295026
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $45,871 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	3	8/6/2026	NON-COMPETING CONTINUATION	$45,871
														Subtotal = $45,871

Issue Date FY: 2025 ( Subtotal = $45,295 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	2	7/29/2025	NON-COMPETING CONTINUATION	$45,295
														Subtotal = $45,295

Issue Date FY: 2024 ( Subtotal = $44,731 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	1	6/21/2024	NEW	$44,731
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	001	1	6/21/2024	NEW	$0
														Subtotal = $44,731

Grand Total All Awards = $135,897

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

Award Number: F31CA295026

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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