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Elucidation of the molecular mechanisms of the RBM15-MKL1 fusion protein in acute megakaryoblastic leukemia

Award Number: F31CA271571
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 01/23/2027

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Elucidation of the molecular mechanisms of the RBM15-MKL1 fusion protein in acute megakaryoblastic leukemia - PROJECT SUMMARY/ABSTRACT Acute megakaryoblastic leukemia (AMKL) is a form of cancer most prevalent in children under four years old. Targeted AMKL-specific treatment options are limited, and survival rates remain variable. A major obstacle to improving therapy options for AMKL is the dearth of data regarding the mechanisms that contribute to AMKL leukemogenesis. Of several known causative genomic alterations in AMKL, the t(1;22) translocation, which encodes the RBM15-MKL1 (RM) fusion protein, is considered a neonatal mutation as it is always diagnosed in children younger than 6 months old. RNA-binding motif protein 15 (RBM15) is required for recruitment to RNA of the N6-methyladenosine (m6A) writer complex and subsequent epitranscriptomic modification of the transcripts. Megakaryoblastic leukemia 1 (MKL1) is a transcriptional coactivator and is involved in gene expression and megakaryocyte maturation. RM retains all functional domains of both proteins and, despite our understanding of these proteins, the properties of RM itself remain poorly understood. The goal of this proposal is to investigate the molecular mechanisms by which RBM15’s association with RNA in the context of the RM fusion protein contributes to leukemogenesis. Based on our preliminary data, we hypothesize that RM alters gene expression via binding to RNA and promoting modification of the epitranscriptome which promotes oncogenesis via aberrant Wnt signalling. To test this hypothesis, two Aims are proposed. The first Aim is to identify RNAs bound and m6A modified by RM using enhanced crosslinking and immunoprecipitation sequencing techniques. This will determine which transcripts are targeted by RM and which adenosine residues are modified following RM binding, and functional analysis will determine pathways important to leukemogenesis. Computational integration with RNA-seq will provide insight into the fate of RNAs targeted by the RM fusion protein in contrast to control RBM15. The second Aim is to investigate the role of candidate proteins in RM- mediated leukemogenesis by knocking down select candidates in a physiologically relevant murine megakaryoblastic cell line model. In vitro and in vivo assessment of leukemogenesis will determine the requirement of these candidates for the survival of leukemia cells in vitro and for maintenance of disease in vivo. These experiments will provide insight into the transcriptomic and epitranscriptomic effects of RM that are critical to the mechanistic function of the fusion protein. A better understanding of the mechanisms driving RM-mediated AMKL will significantly broaden knowledge of AMKL leukemogenesis and provide potential novel therapeutic avenues to improve outcomes and survival rates of neonates with this disease.


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 = $53,114 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	3	12/19/2025	NON-COMPETING CONTINUATION	$52,538
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	001	3	4/16/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $53,114

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	2	12/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $51,474 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	2	7/19/2024	NON-COMPETING CONTINUATION	$51,474
														Subtotal = $51,474

Issue Date FY: 2023 ( Subtotal = $50,194 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	4/14/2023	NEW	$47,694
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	001	1	4/14/2023	NEW	$0
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	002	1	9/19/2023	NEW	$2,500
														Subtotal = $50,194

Grand Total All Awards = $154,782

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Elucidation of the molecular mechanisms of the RBM15-MKL1 fusion protein in acute megakaryoblastic leukemia

Award Number: F31CA271571

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 01/23/2027

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