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Mechanisms of Glucocorticoid Response and Resistance in Lymphoid Malignancies

  • Lauren K. Meyer
  • Michelle L. HermistonEmail author
Chapter
First Online:
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Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 21)

Abstract

Glucocorticoids (GC) are an integral component of multi-agent therapy regimens for a wide variety of lymphoid malignancies due to their potential effects to induce apoptosis in cells of the lymphoid lineage. Despite their clinical utility, de novo and acquired resistance to GC is a significant clinical problem that contributes to inferior outcomes for many of these diseases. This review summarizes what is currently known about mechanisms of GC resistance in lymphoid malignancies, with a particular focus on novel therapeutic strategies currently in preclinical or clinical development that are rationally-designed to overcome GC resistance and improve clinical outcomes.

Keywords

Apoptosis Glucocorticoid Leukemia Lymphoma Metabolism MicroRNA Drug resistance Signal transduction 

Abbreviations

2-DG

2-Deoxy-D-Glucose

3’UTR

3’ Untranslated Region

B-CLL

B-Cell Chronic Lymphocytic Leukemia

BFM

Berlin-Frankfurt-Munster

cAMP

Cyclic Adenosine Monophosphate

CDK

Cyclin Dependent Kinase

ChIP-Seq

Chromatin Immunoprecipitation with Sequencing

CHOP

Cyclophosphamide, Adriamycin, Vincristine, and Prednisone

DBD

DNA Binding Domain

DEX

Dexamethasone

DLBCL

Diffuse Large B-Cell Lymphoma

EFS

Event-Free Survival

GC

Glucocorticoid(s)

GR

Glucocorticoid Receptor

GRE

Glucocorticoid Response Element

GST

Glutathione S-Transferase

HDAC

Histone Deacetylase

HSD

Hydroxysteroid Dehydrogenase

LBD

Ligand Binding Domain

LOH

Loss of Heterozygosity

MAPK

Mitogen Activated Protein Kinase

miR

MicroRNA

MRD

Minimal Residual Disease

NCoR

Nuclear Co-Receptor

NHL

Non-Hodgkin Lymphoma

NTD

N-Terminal Transactivation Domain

PDE

Phosphodiesterase

PDX

Patient-Derived Xenograft

PGR

Prednisone Good Responder

PKA

Protein Kinase A

PPR

Prednisone Poor Responder

RT-PCR

Real-Time Polymerase Chain Reaction

T-ALL

T-Cell Acute Lymphoblastic Leukemia

TCR

T-Cell Receptor

WBC

White Blood Cell

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Notes

Acknowledgements

L.K.M. is supported by the UCSF Medical Scientist Training Program Grant T32 GM007618 and by a Genentech Foundation Award. M.L.H is supported by the National Cancer Institute Grant R01 CA193776, The Campini Foundation, The Buster Posey Family Foundation, and The Pepp Family Foundation. The authors thank Kevin Shannon and Anica Wandler for their critical reading of the manuscript.

Disclosure of Conflict of Interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. 1.Department of PediatricsUniversity of CaliforniaSan FranciscoUSA

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