# Targeting Novel Protein Complexes for the Treatment of Acute Myeloid Leukemia

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $300,200

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite recent advances in the treatment of acute myeloid leukemia (AML), the morbidity and mortality of AML
remains very high and novel therapeutic approaches are urgently needed. This is a competing renewal
application whose overall objective is to define the functional significance of novel protein complexes in AML
cells and to exploit their potential therapeutic targeting. We have identified novel regulatory protein complexes
involving the cyclin dependent kinase 9 (CDK9). We found that CDK9 is a novel binding partner of the mTOR
complex scaffold protein, mLST8 and is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and
nucleus. In the nucleus, CDK9 binds to Raptor and mLST8, forming CTORC1, to promote transcription of
genes important for leukemogenesis. In the cytoplasm, CDK9 binds to Rictor, SIN1 and mLST8, forming
CTORC2 complexes that control mRNA translation through phosphorylation of LARP1 and rpS6. Targeting
CTOR complexes results in suppression of growth of primary human AML progenitors in vitro and generation
strong antileukemic responses in AML xenografts in vivo, suggesting an essential role for CTOR complexes in
the survival of AML leukemic precursors. Specific aim 1 will define the functions of nuclear CTORC1
complexes and mechanisms by which they control expression of genes that promote leukemogenesis. Studies
will be performed to map the interactions between CDK9 and other CTORC1 elements and define mechanisms
by which CTORC1 complexes control transcriptional activation of mitogenic genes and mRNA splicing.
Specific Aim 2 will determine the functions of CTORC2 complexes and their roles in mRNA translation of target
genes and survival of primitive leukemic precursors. Experiments will be performed to define components and
effectors of CTORC2 complexes and their roles in mRNA translation, protein expression, and leukemic cell
survival. Specific aim 3 will examine the antileukemic properties of CTORC1 and CTORC2 targeting on
primary leukemic precursors in vitro and in vivo. It will involve in vitro studies using primary leukemic
progenitors from a large group of AML patients and in vivo experiments using AML mouse models, all aimed to
determine the impact of the different CTOR complexes on leukemogenesis and the potential synergistic effects
of CTORC targeting with other antileukemic agents. Altogether, the studies of this competing renewal
application will advance our understanding of the mechanisms of leukemogenesis and will provide the basis for
important future clinical-translational efforts, involving targeting of CTOR complexes for the treatment of AML.

## Key facts

- **NIH application ID:** 10165511
- **Project number:** 5R01CA121192-13
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** LEONIDAS C. PLATANIAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $300,200
- **Award type:** 5
- **Project period:** 2006-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165511

## Citation

> US National Institutes of Health, RePORTER application 10165511, Targeting Novel Protein Complexes for the Treatment of Acute Myeloid Leukemia (5R01CA121192-13). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10165511. Licensed CC0.

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