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Role of the chromatin regulator HMGA1 in KMT2A-rearranged leukemia

Award Number: F31CA284842
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/03/2024
PERIOD OF PERFORMANCE END DATE: 04/02/2027

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Role of the chromatin regulator HMGA1 in KMT2A-rearranged leukemia - PROJECT SUMMARY/ABSTRACT The objective of this project is to elucidate mechanisms underlying HMGA1 proteins in leukemogenesis and therapy resistance in KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML). KMT2A-r AML is an aggressive form of leukemia that is resistant to current therapies and therefore highly lethal. KMT2A-r leukemia is caused by rearrangements of the KMT2A gene (formerly MLL1), which encode abnormal fusion proteins that drive pro-leukemogenic gene expression, including HOX genes (HOXA9, HOXA10, MEIS1). Despite advances in our knowledge of the fusion partners and proteins that form complexes with KMT2A-r proteins, inhibitors developed to target these fusion proteins or their complexes show only modest efficacy in clinical trials thus far. Moreover, mechanisms underlying KMT2A-r leukemogenesis remain incompletely understood. Thus, there is a dire need for further research and new therapeutic strategies. Here, I propose a novel approach by focusing on the High Mobility Group A1 (HMGA1) chromatin regulator as a fundamental molecular switch required for leukemogenesis and therapy resistance in KMT2A-r AML. Our scientific premise that HMGA1 drives leukemogenesis and therapy resistance in KMT2A-r AML is based on the following preliminary results: 1) HMGA1 is upregulated in KMT2A-r AML with the highest levels after blasts become resistant to therapy, 2) HMGA1 is required for proliferation and clonogenicity in KMT2A-r AML cell lines, 3) HMGA1 binds to the promoter regions and induces expression of leukemogenic HOX genes in KMT2A-r AML cell lines, 4) HMGA1 drives proliferation and represses the CDKN1A tumor suppressor locus in KMT2A-r AML. 5) A recent publication identified CDKN1A repression as a driver of chemoresistance in KMT2A- r AML, although mechanisms underlying its repression were unknown, 6) Prior studies show that treating refractory AML patients with a cyclin-CDK inhibitor (flavopiridol/alvocidib) represses HMGA1 and downstream genes in the patient blasts, suggesting it could target HMGA1 pathways in KMT2A-r AML. Based on these exciting preliminary data, we hypothesize that: 1) HMGA1 drives leukemogenesis and chemoresistance in KMT2A-r AML by directly inducing HOX genes and repressing CDKN1A, and, 2) Targeting HMGA1 will enhance responses to cytotoxic therapy. To test this, we propose the following Specific Aims: 1) To define the role HMGA1 in KMT2A-r leukemogenesis and chemoresistance, and, 2) To determine how HMGA1 induces HOX genes and represses CDKN1A in KMT2A-r AML. Impact: This study will shed light on mechanisms underlying leukemogenesis in KMT2A-r AML and could lead to novel therapeutic strategies. The JHU School of Medicine provides an excellent environment for the PI, Bailey West, to complete the proposed studies. Ms. West will learn cutting-edge techniques, produce first-author manuscripts, and present her work; this training will rigorously prepare her for an academic career.


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 = $50,114 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	3	4/6/2026	NON-COMPETING CONTINUATION	$50,114
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	2	4/11/2025	NON-COMPETING CONTINUATION	$48,974
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	001	2	5/28/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	1	4/3/2024	NEW	$47,694
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	001	1	5/7/2024	NEW	$1,280
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	002	1	5/7/2024	NEW	$0
														Subtotal = $48,974

Grand Total All Awards = $148,626

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Role of the chromatin regulator HMGA1 in KMT2A-rearranged leukemia

Award Number: F31CA284842

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/03/2024

PERIOD OF PERFORMANCE END DATE: 04/02/2027

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