# Mechanisms of Drug Resistance in Acute Myeloid Leukemia

> **NIH NIH R50** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $87,133

## Abstract

PROJECT SUMMARY
Dr. Tamilla Nechiporuk's proposed work will be performed in the laboratory of Dr. Jeffrey Tyner, Unit Director, at
the OHSU Knight Cancer Institute. Under Dr. Tyner's leadership, the Unit recently completed and publicly
released a first wave of Beat AML data, representing a multifaceted collection of information on drug sensitivities
and genomic profiles of 900+ patients with acute myeloid leukemia (AML) and other hematologic malignancies.
The Beat AML project is a multi-center consortium focused on advancing new molecular targeted drug therapies
for the treatment of AML into clinical trials. More recently, with significant contributions from Dr. Nechiporuk, the
Unit began to address a continuous problem of drug resistance, either acquired in relapsed disease or as an up-
front, intrinsic property, which hinders the success of individualized therapies. To propel our mechanistic
knowledge of molecular underpinnings of drug insensitivities and corresponding networks of signaling, Dr.
Nechiporuk is leading a group utilizing non-biased genome-wide CRISPR Cas9 perturbations in AML cell lines
and primary patient cells. To accomplish this objective, Dr. Nechiporuk proposes to interrogate parental sensitive
and drug-exposure-rendered resistant AML cells for loss and gain of sensitivities in a variety of cell lines
representing the diverse genetic background of AML. The goal of the proposed work is 1) to create a library of
data informing mechanisms leading to the development of drug resistance in specific genetic backgrounds, 2) to
expose potential combinatorial or alternative treatments to prevent or combat the development of resistance,
and 3) to reveal unrealized novel drug targets. As laid out in the proposal, Dr. Nechiporuk plans to achieve these
directives by carrying out genome-wide CRISPR Cas9 perturbations targeting patient-derived AML cells exposed
to current cutting edge molecular agents. This approach will reveal mechanisms of drug resistance and
unrealized molecular targets and/or agents to overcome drug resistance and will be significantly aided by
implementing innovated orthogonal CRISPRi/a methodology to streamline and accelerate validations of top hits.
The existing Beat AML dataset and CRISPR-revealed gene essentiality in primary patient cells will further inform
CRISPR nominated pathways/targets and molecular agents for clinical relevance and application. Collectively,
the work proposed here will be a major benefit to the Unit, and will facilitate numerous avenues of mechanistic
validation in the laboratory as well as clinical development of novel therapeutic approaches.

## Key facts

- **NIH application ID:** 10247736
- **Project number:** 5R50CA251708-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** TAMILLA NECHIPORUK
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $87,133
- **Award type:** 5
- **Project period:** 2020-09-01 → 2022-01-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247736

## Citation

> US National Institutes of Health, RePORTER application 10247736, Mechanisms of Drug Resistance in Acute Myeloid Leukemia (5R50CA251708-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247736. Licensed CC0.

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