# Signaling Pathways and Therapeutic Targeting of Leukemic Cells

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

This is a competing renewal application focused on the mechanisms of leukemogenesis and the
identification of new targets for the treatment of acute myeloid leukemia (AML). Developing novel therapeutic
approaches for the treatment of AML is of high clinical translational relevance and importance, as the outcome
for the majority of patients with acute myeloid leukemia (AML) remains very poor, despite recent advances in
the field. The emergence of leukemic cell resistance continues to be a serious problem and identifying
pathways that can be targeted to eliminate leukemia stem cells (LSCs) would be of high relevance and
importance. Work from our laboratory has provided evidence for the existence of negative feedback regulatory
loops in myeloid leukemia cells that are engaged in response to chemotherapy or other antineoplastic agents
and mediate leukemic cell resistance. These include activation of mitogen activated protein kinase (MAPK)
cascades and other regulatory negative feedback loops.
 The kinases MNK1 and MNK2 are key effectors of MAPK pathways and control phosphorylation of the
eukaryotic initiation factor 4E (eIF4E), a key element of the cap-translation initiation complex, whose function
is critical for malignant transformation and survival of neoplastic cells. In addition, work from our group has
provided the first evidence that MNK kinases are activated in a negative feedback regulatory manner to
mediate eIF4E phosphorylation and to promote survival of primitive leukemic precursor cells in AML. Because
of such key roles for eIF4E in tumorigenesis, targeting this signaling cascade using MNK kinase inhibitors may
provide a unique approach to target and eliminate LSCs. The current proposal is a systematic approach to
define the mechanisms by which MNK kinases promote LSC survival in AML and aims to use such information
towards identifying novel cellular elements to selectively target LSCs and develop new therapeutic approaches
for AML. Specific aim 1 will define MNK effector pathways in AML leukemic progenitors and will dissect their
contributions in leukemogenesis. Experiments will be performed to define the roles of MNK-regulated effectors
in controlling oncogenic mRNA translation, processing, cell proliferation, and survival of leukemic precursors.
In addition the differential requirement of MNK1 versus MNK2 in leukemogenesis and their regulatory effects
on downstream pathways will be dissected. Specific Aim 2 will examine the roles of MNK kinases and
effector pathways in antileukemic responses in AML models in vivo. AML mouse models will be established in
single Mnk1-/- or Mnk2-/- or double Mnk1-/-2-/- knockout mice, and the impact of different MNK kinases in
leukemogenesis and generation of antileukemic responses in response to chemotherapy and other
antileukemic agents will be addressed. Similar studies will be performed using mutant eIF4E knock-in mice, in
which eIF4E cannot undergo MNK-mediated phosphorylation. Specific aim 3 examin...

## Key facts

- **NIH application ID:** 9932313
- **Project number:** 5I01CX000916-07
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** LEONIDAS C. PLATANIAS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932313

## Citation

> US National Institutes of Health, RePORTER application 9932313, Signaling Pathways and Therapeutic Targeting of Leukemic Cells (5I01CX000916-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932313. Licensed CC0.

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