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The Role of miR-142 in the Transformation of Clonal Hematopoietic Disorders into AML

Award Number: R01CA258981
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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The Role of miR-142 in the Transformation of Clonal Hematopoietic Disorders into AML - Chronic clonal blood disorders such as myeloproliferative neoplasms (MPN) and chronic phase (CP) chronic myelogenous leukemia (CML) may over time transform, respectively, into secondary (s) acute myeloid leukemia (AML) and blast crisis (BC) CML, which are poorly responsive to currently available therapies, including allogeneic stem cell transplantation. Thus, the availability of novel and more effective treatments is a true unmet need for these patients. MicroRNAs (miRNAs) are small non-coding RNAs that target messenger RNAs and regulate the corresponding protein levels. MIR142, encoding miR-142, is a highly conserved “gene”, expressed at high levels in hematopoietic cells and is involved in the development and function of myeloid, lymphoid and megakaryocyte- erythroid progenitors. MIR142 has been found mutated and/or downregulated both in lymphoma and AML. Furthermore, miR-142 knock-out (KO) causes impaired hematopoiesis in zebra fish and mice, with expansion of hematopoietic stem and progenitor cells (HSPCs) and decreased hematopoietic output. We recently demonstrated that miR-142 KO in mouse models with clonal myeloproliferative disorders (MPDs; i.e., FLT3-ITD+ MPN or CP CML) prompts transformation into an AML-like disease and confers a significantly shorter survival to these animals. Our data support a role of miR-142 deficit in deregulation of the metabolism of clonal hematopoietic stem cells (HSCs), with a switch to higher levels of oxidative phosphorylation (OxPhos) via increased fatty acid oxidation (FAO); these changes likely play a key role in the transformation of clonal HSCs into leukemic stem cells (LSCs). We demonstrated that rescue of miR-142 deficit with a novel miR-142 mimic compound (CpG-M-miR-142) reduced OxPhos levels and viability of LSCs, decreased LSC burden and activity and prolonged survival of treated BC CML mice. Thus, the central hypothesis of this proposal is that the understanding of the cellular and molecular basis of miR-142 downregulation and its impact on the transformation of clonal MPD into aggressive AML-like disease will allow us to design and optimize novel treatments to compensate for the miR-142 deficit and prevent and cure MPD transformation. We propose the following Specific Aims (SAs): SA#1: To define the role of miR-142 deficit in the sAML/BC CML transformation. SA#2: To dissect the molecular mechanisms through which miR-142 deficit contributes to sAML/BC CML transformation. SA#3: To investigate the pharmacokinetic (PK), pharmacodynamic (PD) and therapeutic impact of a synthetic CpG-M-miR-142 that will rescue miR-142 deficit in sAML/BC CML.


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 = $542,890 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	5	4/16/2026	NON-COMPETING CONTINUATION	$54,289
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	12/22/2025	NON-COMPETING CONTINUATION	$488,601
														Subtotal = $542,890

Issue Date FY: 2025 ( Subtotal = $542,890 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	4	12/19/2024	NON-COMPETING CONTINUATION	$488,601
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	4	6/2/2025	NON-COMPETING CONTINUATION	$54,289
2025	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	3	11/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $542,890

Issue Date FY: 2024 ( Subtotal = $515,745 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	3	12/18/2023	NON-COMPETING CONTINUATION	$488,601
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	3	4/18/2024	NON-COMPETING CONTINUATION	$27,144
														Subtotal = $515,745

Issue Date FY: 2023 ( Subtotal = $532,031 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	2	3/14/2023	NON-COMPETING CONTINUATION	$43,430
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	12/22/2022	NON-COMPETING CONTINUATION	$488,601
														Subtotal = $532,031

Issue Date FY: 2022 ( Subtotal = $542,890 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	12/30/2021	NEW	$542,890
														Subtotal = $542,890

Grand Total All Awards = $2,676,446

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The Role of miR-142 in the Transformation of Clonal Hematopoietic Disorders into AML

Award Number: R01CA258981

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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