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Role of lincRNAs in HSC function and leukemogenesis

Award Number: R01HL141950
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Role of lincRNAs in HSC function and leukemogenesis - Abstract Hox genes, especially HOXA and HOXB genes, are critical for maintaining the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs). Dysregulation of HOXA and/or HOXB genes is a dominant mechanism of leukemic transformation. Aberrant HOX gene expression is associated with fusion genes involving MLL1 and NUP98, and mutations in NPM1 and CEBPA. However, the epigenetic mechanisms that regulate HOX gene transcription to control HSC function remain to be explored. Furthermore, it is critical to elucidate how HOX genes are aberrantly activated during leukemogenesis. Better understanding of these critical questions will assist in the development of highly effective and selective targeted therapies. We recently identified a HoxB locus associated long intergenic noncoding RNA (lncRNA), HoxBlinc, which controls hematopoietic lineage commitment and differentiation by organizing CTCF mediated active chromatin domain to facilitate anterior HoxB gene activation. HoxBlinc recruits the Setd1a/MLL1 complexes to activate HoxB genes. We found that HoxBlinc lncRNA is overexpressed in significant portions of AML patients, and AML patients with high HoxBlinc expression had significantly shortened survival compare to patients with low HOCBLINC expression. Furthermore, transgenic expression of HoxBlinc in mice leads to increased pools of LT-HSCs and ST-HSCs, and development of lethal AML-like disease. We hypothesize that HoxBlinc lncRNA is a critical epigenetic regulator of HSCs, by controlling the activation of Hox and other key HSC-regulating genes through modulation of chromatin dynamics. In addition, up-regulation of HoxBlinc may represent a potent oncogenic event in leukemogenesis. To test these hypothesis, we will: 1) determine the role of HoxBlinc lncRNA in HSC biology and behavior by performing serial transplantation and paired daughter cell assays using purified HoxBlinc-Tg HSCs; 2) determine whether transgenic HoxBlinc expression is sufficient to perturb hematopoiesis and cause myeloid malignancies in mice; 3) investigate the mechanism(s) by which HoxBlinc lncRNA regulates behaviors of different stages of HSCs by examining global changes in HoxBlinc chromatin binding, 3D chromatin organization, histone modifications, chromatin accessibility, as well as transcription profiles in HSCs purified from WT and HoxBlinc-Tg mice; 4) examine if the function exerted by HoxBlinc lncRNA in HSCs is dependent on the Setd1a/MLL1 complexes; 5) explore whether HOXBLINC lncRNA can serve as an effective therapeutic target for AMLs by examining whether HoxBlinc loss is capable of mitigating NPM1C+- or other mutation-driven myeloid malignancies via abrogating the signature aberrant HOX gene expression. Success of the proposed studies will result in fundamental knowledge regarding the regulation of HSCs by lncRNAs. Our studies could establish HoxBlinc as a powerful oncogenic lncRNAs during leukemogenesis. HOXBLINC lncRNA might represent a novel therapeutic target for AMLs with high HOXBLINC expression.


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: 2024 ( Subtotal = -$14,545 )
2024	2022	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Blood Diseases and Resources Research	000	4	5/13/2024	NON-COMPETING CONTINUATION	-$14,545
														Subtotal = -$14,545

Issue Date FY: 2022 ( Subtotal = $532,517 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Blood Diseases and Resources Research	000	4	12/6/2021	NON-COMPETING CONTINUATION	$479,264
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Blood Diseases and Resources Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$53,253
														Subtotal = $532,517

Issue Date FY: 2021 ( Subtotal = $535,341 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Blood Diseases and Resources Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$53,535
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Blood Diseases and Resources Research	000	3	12/7/2020	NON-COMPETING CONTINUATION	$481,806
														Subtotal = $535,341

Issue Date FY: 2020 ( Subtotal = $555,453 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Blood Diseases and Resources Research	003	2	5/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$379,930
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Blood Diseases and Resources Research	001	2	2/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$555,453
2020	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Blood Diseases and Resources Research	002	1	5/5/2020	NEW	-$379,930
2020	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Blood Diseases and Resources Research	000	1	2/3/2020	NEW	$0
														Subtotal = $555,453

Issue Date FY: 2019 ( Subtotal = $557,193 )
2019	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Blood Diseases and Resources Research	000	1	12/28/2018	NEW	$557,193
														Subtotal = $557,193

Grand Total All Awards = $2,165,959

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Role of lincRNAs in HSC function and leukemogenesis

Award Number: R01HL141950

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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