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mRNA stability and its impact on hematopoiesis and acute leukemia

Award Number: R01CA266212
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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mRNA stability and its impact on hematopoiesis and acute leukemia - Abstract This application focuses on acute myeloid leukemia (AML), a blood cancer that is characterized by low survival rates and few available targeted therapies. The five-year overall survival rate for AML is below 30 percent in adults and around 65% in children. Interestingly, one type of intervention that has been successful for a subtype of AML (acute promyelocytic leukemia, APL) is a “differentiation” therapy, where drugs can induce tumor cell differentiation and apoptosis. Here we present surface antigen- guided, CRISPR/CAS9 differentiation screens in AML and study one of the most prominent hits in these screens, the RNA binding protein (RBP) ZFP36L2. RBPs can modify RNA at multiple levels, including splicing, processing, modification and degradation. Considering that RBPs are key regulators of gene expression, alterations of these proteins are also implicated in several human genetic diseases, including cancer. Our laboratory has recently presented CRISPR/CAS9 screening of RBPs in several types of human leukemia and identified novel regulators of the spliceosome machinery in blood cancers. Our CRISPR screens identified ZFP36L2, a member of the TIS11/TTP zinc-finger containing family of RBPs, that also includes the ZFP36 and ZFP36L1 paralogs. We were able to show that ZFP36L2 binds AU-rich elements on 3’ untranslated regions (UTRs) of a number of mRNAs that that control early hematopoietic and myeloid differentiation. This interaction promotes target mRNA degradation and the maintenance of an undifferentiated state. These studies showed that ZFP36L2 can bind and degrade the two other members of the TIS11/TTP family, ZFP36 and ZFP36L1, creating a potential additional level of post-transcriptional regulation of differentiation. Inhibition of ZFP36L2 restores mRNA stability of targeted transcripts and triggers leukemia cells to undergo myeloid differentiation and eventual apoptosis. Epigenomic profiling of a number of primary AML patients revealed enhancer modules nearby ZFP36L2 that associated with distinct AML cell states, establishing a coordinated epigenetic and post-transcriptional mechanism that shapes leukemic differentiation. In this application we initially (Aim 1) focus on the in vivo role of ZFP36L2 in AML and identify mRNAs, direct targets that can control AML cell differentiation and growth. In Aim 2, we study all three members of the ZFP36/TIS11 family and study in detail their roles in hematopoiesis and myeloid leukemia.


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 = $486,121 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	5	1/6/2026	NON-COMPETING CONTINUATION	$486,121
														Subtotal = $486,121

Issue Date FY: 2025 ( Subtotal = $540,134 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	4	6/6/2025	NON-COMPETING CONTINUATION	$54,013
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	4	12/18/2024	NON-COMPETING CONTINUATION	$486,121
														Subtotal = $540,134

Issue Date FY: 2024 ( Subtotal = $513,127 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$27,006
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	3	12/21/2023	NON-COMPETING CONTINUATION	$486,121
														Subtotal = $513,127

Issue Date FY: 2023 ( Subtotal = $529,332 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	001	2	3/15/2023	NON-COMPETING CONTINUATION	$43,211
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	2	12/22/2022	NON-COMPETING CONTINUATION	$486,121
														Subtotal = $529,332

Issue Date FY: 2022 ( Subtotal = $540,134 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Biology Research	000	1	12/21/2021	NEW	$540,134
														Subtotal = $540,134

Grand Total All Awards = $2,608,848

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mRNA stability and its impact on hematopoiesis and acute leukemia

Award Number: R01CA266212

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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