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The Novel Role and Mechanism of RBM33 in Leukemogenesis

Award Number: R01CA266659
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/17/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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The Novel Role and Mechanism of RBM33 in Leukemogenesis - Abstract Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematological malignancies caused by gene mutations and genomic rearrangements. The cure rates for AML patients have not significantly improved for decades. The molecular mechanisms underlying the pathogenesis of AML are not fully understood. By analysis of publicly available genomic data using a new machine learning approach, RNA Binding Motif Protein 33 (RBM33), an RNA binding protein, is identified as an essential gene in AML. However, the biological function of RBM33 is unknown yet. Our preliminary studies provide the first compelling evidence suggesting a novel function of RBM33 in regulating m6A RNA demethylation. More importantly, we showed that RBM33 knockdown significantly inhibited growth and survival of human and mouse leukemia cells. At a molecular level, we have identified a potential downstream target of RBM33 in leukemia cells. ALKBH5 is known as an m6A mRNA demethylase (Eraser), which removes m6A methylated groups from RNA. To date, it remains unknown whether another member of RNA binding proteins is required for ensuring recruitment of ALKBH5 to its mRNA targets. We have recently demonstrated that ALKBH5 has a critical role in AML development and maintenance. We hypothesize that RBM33 plays a critical role in the pathogenesis of AML by regulating ALKBH5-mediated m6A demethylation. To test this hypothesis, we will pursue three specific aims. In Aim1, we will determine a novel role of RBM33 in regulation of dynamic m6A RNA methylation in leukemia cells. In Aim2, we will investigate the role of Rbm33 in AML development and maintenance. In Aim 3, we will determine the downstream pathway that mediates the function of RBM33 in leukemogenesis in AML. We will employ both mouse genetic models as well as human patient-derived mouse models to elucidate the role of RBM33 in normal hematopoiesis and leukemogenesis in vivo, and will combine transcriptome and epitranscriptome analysis to identify the key downstream targets and associated downstream pathways that mediate the role of RBM33 in leukemogenesis. Our studies will uncover a novel role of RBM33 in m6A RNA modification, and define the importance and underlying mechanisms of RBM33 in AML development and maintenance as well as LSC/LIC self-renewal. Thus, the success of our project will significantly advance our understanding of the complex mechanisms underlying the m6A modification-mediated gene regulation in leukemia cells and the critical role of m6A RNA demethylation in leukemogenesis.


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 = $22,408 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	4	7/16/2025	NON-COMPETING CONTINUATION	$22,408
														Subtotal = $22,408

Issue Date FY: 2024 ( Subtotal = $385,748 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	3	3/18/2024	NON-COMPETING CONTINUATION	$365,444
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$20,304
														Subtotal = $385,748

Issue Date FY: 2023 ( Subtotal = $397,927 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	2	3/24/2023	NON-COMPETING CONTINUATION	$397,927
														Subtotal = $397,927

Issue Date FY: 2022 ( Subtotal = $406,049 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	1	5/17/2022	NEW	$406,049
														Subtotal = $406,049

Grand Total All Awards = $1,212,132

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The Novel Role and Mechanism of RBM33 in Leukemogenesis

Award Number: R01CA266659

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/17/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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