# Transporters and hematopoietic toxicity

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $484,566

## Abstract

Abstract
Future improvements in acute myeloid leukemia (AML) therapy will require treatments that more effectively
eradicate leukemia, while at the same time reduce the severity of chemotherapeutic side effects such as
bleeding due to thrombocytopenia. The proposed project will focus on both of these issues. One approach to
improving AML chemotherapy is to identify key differences in proteins that impact the function of important
transporters in AML. We propose that the vulnerability of AML to both conventional and newer targeted
chemotherapy can be exploited by identifying key proteins that affect the function of the ABC transporter,
ABCC4, a protein highly expressed in AML. Our preliminary data reveal that MPP1, a PDZ-binding protein that
is highly expressed in AML physically interacts with ABCC4 through its PDZ-motif. Importantly, high
expression of MPP1 is a poor prognostic factor in AML. A central hypothesis driving our proposal is that the
protein interaction between ABCC4 and MPP1, mediated by ABCC4-PDZ motif, is crucial to the MPP1 driven
hematopoietic progenitor transformation as well as ABCC4 mediated export of chemotherapeutic drugs. Our
second hypothesis relates to a novel mechanism impacting platelet production. This hypothesis was based
upon recent GWAS studies that identified ABCC4 as one of the novel genetic determinants of platelet
formation during megakaryopoiesis (platelet formation) (2, 7). It is unknown if ABCC4 has a role in
megakaryopoiesis. We propose highly integrated studies that focus on the ABCC4 transporter, a protein that
is expressed megakaryocytes, the cell responsible for the genesis of platelets. (1) Using both in vitro and in
vivo AML models and cell lines, we will investigate how ABCC4 and MPP1 interact to produce
transformation/immortalization of hematopoietic progenitors as well as confer resistance to chemotherapeutic
drugs in AML, (2) Determine the domains of MPP1 required to alter ABCC4 function, and (3) Elucidate how
ABCC4 regulates the formation of platelets from megakaryocytes.

## Key facts

- **NIH application ID:** 9937676
- **Project number:** 5R01CA194206-05
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** JOHN D SCHUETZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $484,566
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937676

## Citation

> US National Institutes of Health, RePORTER application 9937676, Transporters and hematopoietic toxicity (5R01CA194206-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9937676. Licensed CC0.

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