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Targeting MBNL1-mediated alternative splicing in MLL-fusion leukemia

Award Number: K08CA237753
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/25/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Targeting MBNL1-mediated alternative splicing in MLL-fusion leukemia - Proposal Summary/Abstract: Though outcomes for pediatric acute leukemia have improved dramatically over the last few decades, infant leukemia is a particularly aggressive disease which remains difficult to cure even with chemotherapy intensification and bone marrow transplant. Most of these leukemias carry a rearrangement of the MLL gene, a phenomenon also seen in some de novo acute myeloid leukemias (AML) as well as therapy-related AML, and studies have demonstrated that a common gene expression program underlies these leukemias regardless of lineage. Through preliminary studies, we have found that MLL-fusion leukemias express high levels of MBNL1, an RNA binding protein that regulates alternative RNA splicing. We have also identified an alternative splicing (AS) signature unique to MLL-fusion leukemia, and show that MBNL1 loss causes reversion of this signature and impairs MLL-fusion leukemia cell growth. We thus hypothesize that MBNL1 is a critical regulator of an MLL-fusion specific AS program, and that disruption of this program via MBNL1 inhibition leads to leukemia cell death. To test these hypotheses, our specific aims are 1) to determine the mechanism underlying MLL-fusion leukemia dependence on MBNL1, and 2) optimize characteristics of a small-molecule MBNL1 inhibitor as a treatment for MLL-fusion leukemia. To achieve the first aim, we will characterize changes in key cell growth and death pathways which we hypothesize are responsible for the effects seen with genetic knockdown. We will also identify novel MBNL1-mRNA interactions in MLL-fusion leukemia using CLIP-seq (cross-linking immunoprecipitation with RNAseq). For the second aim, we have shown as a proof of concept that a small molecule inhibitor of MBNL1 can induce MLL-fusion leukemia cell death. This compound requires optimizations for potency, which we will achieve by applying medicinal chemistry principles. Furthermore, we have used its structural characteristics and published crystal structures to initiate an in silico screen of a proprietary compound library. This proposal will advance our understanding of the role of AS in the pathogenesis of MLL-fusion leukemia, while also directly leading to a first-in-class therapy for this disease. The applicant, who is currently an instructor in the Division of Oncology at Cincinnati Children’s Hospital Medical Center, will execute this research plan while simultaneously engaging in structured didactics and receiving close individual guidance from a panel of mentors as described in the application. These scientists possess significant expertise in the molecular pathogenesis of leukemia. The experiments, mentoring, and structured classwork described in this career development plan will position the applicant to successfully transition into an independent researcher and physician-scientist, with expertise in the role of RNA binding proteins in leukemia pathogenesis.


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 = $196,112 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Research Manpower	000	5	2/13/2025	NON-COMPETING CONTINUATION	$196,112
														Subtotal = $196,112

Issue Date FY: 2024 ( Subtotal = $196,112 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Research Manpower	000	4	2/9/2024	NON-COMPETING CONTINUATION	$196,112
														Subtotal = $196,112

Issue Date FY: 2023 ( Subtotal = $196,112 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Research Manpower	000	3	2/23/2023	NON-COMPETING CONTINUATION	$196,112
														Subtotal = $196,112

Issue Date FY: 2022 ( Subtotal = $196,112 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Research Manpower	000	2	2/11/2022	NON-COMPETING CONTINUATION	$196,112
														Subtotal = $196,112

Issue Date FY: 2021 ( Subtotal = $196,112 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Research Manpower	000	1	3/25/2021	NEW	$196,112
														Subtotal = $196,112

Grand Total All Awards = $980,560

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Targeting MBNL1-mediated alternative splicing in MLL-fusion leukemia

Award Number: K08CA237753

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/25/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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