# STEROID RESISTANCE IN HUMAN LEUKEMIC CELLS

> **NIH NIH R01** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 1993 · $198,327

## Abstract

The objective of this investigation remains the elucidation of the basis
for the acquisition of glucocorticoid resistance in the human leukemic
cell line CEM-C7.  Specific mutations responsible for loss of
glucocorticoid receptor (GR) function in spontaneously occurring
glucocorticoid-resistant (dex-r) mutants will be cloned and sequenced to
determine whether they are randomly distributed throughout the human GR
(hGR) gene, or are localized to specific regions.  Transient transfection
assays will be used to ascertain whether any of these mutants act as
dominant negative repressors of receptor function.  Restriction fragment
length polymorphisms in the 5' and 3' regions of the hGR gene will be
used to assess the frequency, extent, and distribution of deletions in
the hGR gene in dex-r mutants induced by cytotoxic cancer
chemotherapeutic drugs with different mechanisms of action to determine
if specific regions of the hGR gene are particularly susceptible to
breakage, and whether individual drugs have specific mutagenic
"signatures."

The pathway of steroid-induced growth arrest will be investigated.  The
basis for tissue-specific autoregulation of hGR expression will be
determined by isolation, and functional characterization of hGR promoter
regions responsible for hGR regulation in T and B cells.  The role of
positive autoregulation of hGR expression in steroid-induced cell death
will be evaluated by stable transfection of an hGR gene under the control
of the metal-inducible mouse metallothionein I gene promoter into cells
lacking endogenous functional hGR. hGR concentration will be correlated
with growth arrest to determine whether positive autoregulation is a
necessary component in growth arrest or simply a pleiotypic response.  In
addition, construction of subtractive cDNA libraries will be used to
attempt to isolate other genes involved in steroid-induced growth arrest.

Identification of the mutations responsible for loss of hGR function in
spontaneously occurring and drug-induced dex-r mutants will provide new
information about the function of this trans-acting regulator of gene
expression.  In addition, an understanding of mechanisms responsible for
the growth arrest of glucocorticoid-sensitive human leukemic cells in
culture, and the mechanisms responsible for the acquisition of steroid
resistance could provide the foundation for similar studies in steroid
resistant leukemias, thus permitting the determination of when steroid
treatment would be beneficial, and when such treatment and its associated
side effects would best be withheld.

## Key facts

- **NIH application ID:** 3170194
- **Project number:** 2R01CA032226-12
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **SAM.gov UEI:** UYLKBRENAPG5
- **Principal Investigator:** JEFFREY M HARMON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $198,327
- **Award type:** 2
- **Project period:** 1988-08-01 → 1997-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3170194

## Citation

> US National Institutes of Health, RePORTER application 3170194, STEROID RESISTANCE IN HUMAN LEUKEMIC CELLS (2R01CA032226-12). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3170194. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*