The purpose of this modification is to (1) change the Principal Investigator from Yan Liu to James Croop, per the recipient’s request dated 03/12/2021; (2) add a subaward to Northwestern University effective 04/01/2021, per the recipient’s request dated 03/12/2021; & (3)extended the period of performance by 12 months at no additional cost to the Government, per recipient request dated 02/17/2021. The revised spend plan dated 04/07/2021 is incorporated herein by reference. The 2nd annual technical report is due no later than 08/31/2021. The final technical report is due no later than 11/30/2022. Submissions of the financial reports (SF425s) shall continue during the no-cost extension period. Specific Aims: Aim 1 will determine the impact of genetic and pharmacological inhibition of PRL2 on leukemiainitiating cells. We hypothesize that inhibition of PRL2 activity will decrease LIC self-renewal and survival. Aim 2 will determine the mechanisms by which PRL2 contributes to the pathogenesis of leukemia. We hypothesize that PRL2 inhibits the E3 ligase activity of CBL toward KIT and FLT3, leading to decreased ubiquitination and degradation of KIT and FLT3, and activation of signaling pathways in leukemia cells. Study Design: In Aim 1, we will test the effects of genetic and pharmacological inhibition of PRL2 on LIC self-renewal and survival by employing a mouse model of human AML and Patient-Derived Xenograft (PDX) models. We expect that the findings from this set of experiments will further validate PRL2 as a putative therapeutic target for patients with MLL leukemias. In Aim 2, we will elucidate the mechanisms by which PRL2 enhances the activation of KIT and FLT3 in LICs. We expect that the findings from Aim 2 will establish KIT and FLT3 as therapeutic targets for therapeutic intervention in MLL leukemias highly expressing PRL2. Grants Specialist: Darrell Beaver Phone: 301-619-4019 Email: Darrell.L.Beaver4.email@example.com Assistance Agreement Branch Email: firstname.lastname@example.org W81XWH1910575 Grants Officer’s Representative Congressionally Directed Medical Research Program Office Phone: 301-619-7071 Email: email@example.com
|Effective start/end date||4/1/21 → 7/31/22|
- Indiana University (9101//W81XWH1910575)
- U.S. Army Medical Research and Materiel Command (9101//W81XWH1910575)
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