Role of hottip/beta-catenin-HOXA9/PRMT1 axis in hematopoietic and leukemic stem cells
Active Project Grant Awarded Last action
- Award ID
- R01CA264932
- Recipient
-
Pennsylvania State University UEI TNKGNDAWB445 Part of The Pennsylvania State University
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $3,522,269
Award facts
- Assistance listing
- 93.396 Cancer Biology Research
- Completion date 86% complete
- Place of performance
- Hershey, PA 17033, USA
Award details come from USAspending.gov.
Description
- Abstract
- Self-renewal is an indispensable property that allows stem cells to regenerate and maintain the homeostasis of functionally diverse cell populations. Dergulation of self-renewal in hematopoietic stem cell (HSC) directly links to a number of hematopoietic degenerative disorders including bone marrow failure and various blood diseases, whereas its aberrant activation is a defining and indispensable feature of leukemia stem cells (lscs) that sustain the malignant phenotypes. We and others have shown that self-renewal of acute myeloid leukemia (AML) stem cells heavily rely on the key component of canonical WNT signaling pathway, SS-catenin and the homeobox protein, HOXA9 that are largely dispensable for adult hscs. Although these findings reveal a contrasting functional requirement and a potential therapeutic opportunity for AML, development of small molecule inhibitors against oncogenic transcription factors has so far met with very little success largely due to our lack of understanding about the molecular regulations of these proteins in mediating hematopoietic self-renewal, which has significantly hindered progress in developing effective therapeutic strategies to treat the resultant diseases. Intriguingly, we have recently revealed coregulation of both canonical WNT pathway and posterior hoxa loci including HOXA9 by the long non-coding RNA (lncrna), hottip. Strikingly, we also report a novel crosstalk between SS-catenin and HOXA9 that can override their individual requirement in both mouse and human AML of HSC origins. In search for crucial mediators for SS-catenin and HOXA9 functions, we further identified that protein arginine methyltransferase 1 (PRMT1), which also implicates in DNA damage and repair (DDR), can functionally replace HOXA9 or SS-catenin in AML stem cell originated from hscs. PRMT1 together with DDR complex are unbiasedly isolated along with ctcf/cohesin complex, hematopoietic transcription factors (TFS) and nucleosome remodeling factors as hottip interacting partners by chirp-MS in AML cells. These findings not only discover a novel hottip/SS-catenin-HOXA9/PRMT1 axis critical for mediating hematopoietic self-renewal, but also lead to central hypothesis that hottip/SS-catenin-HOXA9/PRMT1 axis coordinates hematopoietic self-renewal and characterization of the functions of individual components and their crosstalk along the axis regulates hematopoietic specific transcription networks and DDR pathways to modulate hematopoietic self-renewal in the disease setting. In this proposal, we will 1 decipher cooperative action of hottip and hematopoietic TFS in regulating HOXA9 and SS-catenin axis; 2) dissect the molecular functions and regulation of SS-catenin- HOXA9/PRMT1 axis during normal and malignant hematopoiesis. Success completion of proposed studies not only will establish the molecular principles, but also facilitate the design of specific therapeutics in modulating self-renewal activities in normal and malignant stem cells, which can be potentially translated into patient benefits.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $202,989 | |
| Amendment | $303,207 | |
| Amendment | $202,540 | |
| Amendment | $303,207 | |
| Amendment | $479,644 | |
| Amendment | $495,056 | |
| Amendment | $495,056 | |
| Amendment | $520,285 | |
| Original award | $520,285 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| King's College London | $202,540 | |
| King's College London | $191,595 |
Quick answers
Who received award R01CA264932?
R01CA264932 was awarded to Pennsylvania State University by National Cancer Institute (National Institutes of Health) on July 1, 2022.
How much is award R01CA264932 worth?
$3,522,269 has been obligated on R01CA264932.
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