Wednesday, September 17, 2025 9/17/2025

TET2-mediated epitranscriptomic regulation in leukemia microenvironment

Award Number: R01CA280389
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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TET2-mediated epitranscriptomic regulation in leukemia microenvironment - PROJECT SUMMARY: Background: Acute myeloid leukemia (AML) is one of the most aggressive types of hematopoietic malignancies with various genetic alterations. Ten-Eleven Translocation 2 (TET2), an enzyme involved in DNA demethylation, is deleted or mutated in 15-20% of AML patients. Those patients with TET2 deficiency are poorly responsive to currently available therapeutic regimens, leading to more adverse outcomes than patients with other AML subtypes. Thus, it is urgent to identify new therapeutic target(s) and develop novel effective approaches to treat TET2-deficient AMLs. Tet2 loss in mice facilitates the self-renewal of hematopoietic stem cells (HSCs) and leukemic stem/initiating cells (LSCs/LICs). The LSCs/LICs reside in a specialized microenvironment called “niche” in the bone marrow (BM) to support their survival and self-renewal. There are several critical gaps in our current knowledge of the molecular mechanism underlying LSC/LIC homing and of the role of TET2 deficiency in the BM microenvironment. Meanwhile, evidence is emerging to support a novel function for TET2-mediated oxidation of methyl-5-cytosine (m5C) in RNAs, including messenger RNA (mRNA). However, it is unknown whether and (if so) how TET2-mediated RNA m5C demethylation contributes to leukemogenesis. Our preliminary study showed that Tet2 deficiency stimulates the Tetraspanin 13 (Tspan13)/C-X-C motif chemokine receptor 4 (Cxcr4) axis to facilitate AML homing/migration into the BM microenvironment, giving rise to increased LSC/LIC self-renewal and fast leukemogenesis in vivo. Tet2 deficiency-mediated increase of mRNA m5C modification in Tspan13 is recognized by Y-box binding protein 1 (YBX1), which in turn stabilizes Tspan13 transcript and increases its expression, thereby activating the Cxcr4 signaling. Pharmacological inhibition of CXCR4 suppresses LSC/LIC homing into the BM microenvironment and shows a synergistic effect with hypomethylating agents in killing TET2-deficient AMLs. These results lead to our central hypothesis that TET2-mediated mRNA m5C demethylation is involved in reprogramming BM microenvironment. Guided by strong preliminary data, we propose three Specific Aims to test our hypothesis: (1) Determine the definitive role of TET2 in the homing of LSCs/LICs into BM microenvironment; (2) Characterize the mRNA m5C-dependent and functionally essential targets of TET2 and decipher the molecular mechanisms underlying the role of TET2 in LSC/LIC homing and self-renewal; and (3) Assess the therapeutic potential of targeting the TET2/CXCR4 axis in high-risk TET2-deficient AMLs. Overall, our proposed studies will substantially advance our understanding of the fundamental biology of TET2-mediated epitranscriptomic changes in BM microenvironment and may result in the development of novel effective approaches to treat AMLs with TET2 deficiency. Thus, our project is of high novelty and significance in both basic research and translational medicine.


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 = $684,584 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	3	8/18/2025	NON-COMPETING CONTINUATION	$684,584
														Subtotal = $684,584

Issue Date FY: 2024 ( Subtotal = $650,167 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	2	8/5/2024	NON-COMPETING CONTINUATION	$650,167
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	1/12/2024	NEW	$0
														Subtotal = $650,167

Issue Date FY: 2023 ( Subtotal = $684,230 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	9/21/2023	NEW	$684,230
														Subtotal = $684,230

Grand Total All Awards = $2,018,981

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TET2-mediated epitranscriptomic regulation in leukemia microenvironment

Award Number: R01CA280389

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/21/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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