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Elucidating the Molecular Pathogenesis of PICALM::MLLT10 Pediatric Acute Myeloid Leukemia

Award Number: F31CA306257
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/21/2025
PERIOD OF PERFORMANCE END DATE: 07/20/2028

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Elucidating the Molecular Pathogenesis of PICALM::MLLT10 Pediatric Acute Myeloid Leukemia - Project Summary Pediatric acute myeloid leukemia (pAML) is the second most common pediatric leukemia accounting for approximately 15-20% of all leukemia diagnoses. Our lab conducted a systemic transcriptomic and genomic analysis of 887 pediatric AML cases and identified 23 distinct molecular categories of pAML varying in HOXA/HOXB cluster gene expression signatures, co-occurring mutations, and overall outcome. From this study, the t(10;11)(p12;q14) chromosomal translocation resulting in the PICALM::MLLT10 fusion oncoprotein is particularly interesting due to its similar HOXA expression profile as the KMT2Ar category, but its distinct cluster identity with other immature AML on a UMAP plot suggesting an alternative transcription profile for these leukemias. This understudied molecular subtype is associated with poor prognosis, therapy resistance, and high relapse rates, emphasizing the urgent need for mechanistic insights to inform therapeutic strategies. This research proposal seeks to elucidate the molecular mechanism by which the PICALM::MLLT10 fusion oncoprotein initiates leukemogenesis and define the PICALM::MLLT10 proteomic interactome to identify potential therapeutic vulnerabilities. Aim 1 of this proposal will address the impact of PICALM::MLLT10 fusion oncoprotein expression on cellular transformation in hematopoietic stem and progenitor cells (HSPCs). I will use a lentiviral overexpression approach in HSPCs to introduce PICALM::MLLT10 or control vectors, and I will study the in vitro consequences of the PICALM::MLLT10 fusion oncoprotein on cellular transformation using a colony- forming unit assay and immunophenotyping by flow cytometry. I will perform RNA sequencing, Cleavage Under Targets and Release Using Nuclease (CUT&RUN), and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to integrate the gene expression profiles, DNA binding properties and histone modifications, and regions of active chromatin, respectively, that accompany expression of PICALM::MLLT10. This multi-omic approach will provide a robust dataset for the investigation of gene-regulatory effects of the PICALM::MLLT10 fusion oncoprotein for validation of functional consequences. Aim 2 of this proposal will use proteomics to identify protein-protein interactions in PICALM::MLLT10 cells as well as the functional validation to evaluate the consequences of the PICALM::MLLT10-protein interactions on leukemic transformation. Specifically, PICALM::MLLT10-protein interactions on chromatin will be assessed using Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME). Top protein hits will be functionally validated using either CRISPR-Cas9 or chemical inhibition. Overall, these studies will elucidate the molecular consequences of the PICALM::MLLT10 fusion oncoprotein in pediatric AML and reveal novel pathways and dependencies that may be interrogated for therapeutic benefit, while providing me with extensive training in cancer biology and multi-omic data analysis, critical skills for my development as an independent scientist.


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: 2025 ( Subtotal = $48,538 )
2025	2025	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	1	7/21/2025	NEW	$48,538
														Subtotal = $48,538

Grand Total All Awards = $48,538

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Elucidating the Molecular Pathogenesis of PICALM::MLLT10 Pediatric Acute Myeloid Leukemia

Award Number: F31CA306257

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/21/2025

PERIOD OF PERFORMANCE END DATE: 07/20/2028

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