# Enhancing FLT3 inhibitor efficacy in acute myeloid leukemia with FLT3-ITD

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2022 · —

## Abstract

Acute myeloid leukemia (AML), the common type of acute leukemia in adults, is an important health
concern for Veterans due to its high incidence and frequent poor response to treatment. Internal tandem
duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is present in AML cells of
30% of patients and is associated with poor treatment outcomes. FLT3 inhibitors have activity, but responses
are limited and transient, with rapid development of resistance occurring by diverse mechanisms.
 FLT3-ITD causes constitutive FLT3 signaling, which is also aberrant. In addition to activating the
PI3K/AKT/mTOR and MEK/ERK/RAS pathways, which are activated by signaling of wild-type FLT3, FLT3-ITD
activates signal transducer and activation of transcription (STAT) 5, which transcriptionally upregulates the
oncogenic serine threonine kinase Pim-1. Pim-1 contributes directly to the proliferative and anti-apoptotic
effects of FLT3-ITD, and also phosphorylates and stabilizes FLT3, promoting STAT5 signaling in a positive
feedback loop in cells with FLT3-ITD. Cells with FLT3-ITD also exhibit inactivation of the serine/threonine
phosphatase protein phosphatase 2A (PP2A), which has tumor suppressor activity. The transcription factor c-
Myc is transcriptionally upregulated downstream of FLT3-ITD, along with Pim-1, and knockdown of c-Myc or
Pim-1 has anti-proliferative effects in cells with FLT3-ITD. In addition, PP2A and Pim-1 both regulate c-Myc
post-translationally. We hypothesize that concurrent targeting of aberrant signaling pathways will enhance the
efficacy of FLT3 inhibitors and prevent development of resistance to FLT3 inhibitors, and overcome resistance.
 Mechanisms of acquired resistance to FLT3 inhibitors include development of point mutations in the FLT3
kinase domain, a FLT3-dependent mechanism, and of RAS mutations - a FLT3-independent mechanism.
Expression of Pim kinases is also further upregulated in cells with FLT3-ITD with FLT3 inhibitor resistance.
 Work in our prior VA Merit Award focused on cellular and molecular effects of pan-Pim kinase inhibition in
 AML cells with FLT3-ITD. Pim inhibition has little effect by itself, but potentiates the anti-proliferative and pro-
 apoptotic effects of FLT3 inhibitors and of chemotherapy drugs in cells with FLT3-ITD. We found that Pim
 inhibition enhances induction of apoptosis of AML cells with FLT3-ITD by FLT3 inhibitors in vitro and in vivo
 via post-translational downregulation of the anti-apoptotic protein Mcl-1 and its deubiquitinase USP9X. We
 subsequently found that post-translational c-Myc downregulation precedes these changes. We also found
 that concurrent treatment of cells with FLT3-ITD with PP2A-activating drugs and FLT3 inhibitors causes
post-translational downregulation of c-Myc and Pim-1; and that these effects are mediated by AKT
 inactivation-dependent activation of GSK-3 which phosphorylates both c-Myc and Pim-1, enhancing their
 proteasomal degradation.
 The ove...

## Key facts

- **NIH application ID:** 10433904
- **Project number:** 5I01BX005120-02
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** MARIA R BAER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433904

## Citation

> US National Institutes of Health, RePORTER application 10433904, Enhancing FLT3 inhibitor efficacy in acute myeloid leukemia with FLT3-ITD (5I01BX005120-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10433904. Licensed CC0.

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