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Anticancer Effects of Intermittent Hypoxia in Acute Myeloid Leukemia

  • Guo-Qiang ChenEmail author
  • Wei Liu
Chapter

Abstract

Acute myeloid leukemia (AML), a commonly developed heterogenous group of hematopoietic malignancies, is characterized by maturation/differentiation block at specific stages during the hematopoietic development. Recently, we reported that moderate hypoxia and hypoxia-mimetic agents could induce the differentiation of human AML cells in culture. Also, hypoxia-mimetic agents enhance differentiation in acute promyelocytic leukemic cells induced by arsenic trioxide (As2O3). In vivo studies show that intermittent hypoxia significantly prolongs the survival of transplanted leukemic mice with inhibition of infiltration and differentiation induction of leukemic cells. Further investigations explore the role of hypoxia-inducible factor-1alpha (HIF-1α) in differentiation of myeloid leukemic cell, in which HIF-1α physically interact with so as to increase the activities of two critical hematopoietic transcription factors, CCAAT/enhancer binding protein alpha (C/EBPα) and Runt-related transcription protein 1(Runx1), whereas C/EBPα competes with HIF-1β and significantly inhibits the DNA-binding ability of HIF-1. Besides, HIF-1α has been shown to play a part in all-trans retinoic acid (ATRA)-induced differentiation of leukemic cells. Therefore, these observations disclose the two-edged sword effect of hypoxia/HIF-1α. Additional investigations may uncover ways to mimic the differentiative effects of hypoxia in a manner that will benefit human patients with AML.

Keywords

Acute Myeloid Leukemia U937 Cell Acute Promyelocytic Leukemia Acute Myeloid Leukemia Patient Intermittent Hypoxia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AML

Acute myeloid leukemia

AML1

Acute myeloid leukemia-1

ARNT

Aryl-hydrocarbon receptor nuclear transporter

As2O3

Arsenic trioxide

ATRA

All-trans retinoic acid

BM

Bone marrow

C/EBPa

CCAAT/enhancer binding protein alpha

CoCl2

Cobalt chloride

Co-IP

Coimmunoprecipitation

DFO

Desferrioxamine

EMSA

Electrophoretic mobility shift assay

FACS

Flow cytometry analysis

HIF-1α

Hypoxia-inducible factor-1alpha

HRE

Hypoxia-responsive element

HSCs

Hematopoietic stem cells

IL1RA

Interleukin-1 receptor antagonist

LacO array

Lac operator heterochromatic array, Operator (LacO) heterochromatic array

NCF1

Neutrophil cytosolic factor-1

ODD

Oxygen-dependent degradation domain

PHDs

Prolyl hydroxylases

PML-RARα

Promyelocytic leukemia-retinoic acid receptor alpha

PODs

PML oncogenic domains

Runx1

Runt-related transcription protein 1

shRNAs

Short-hairpin RNAs

SPP1

Secreted phosphoprotein 1

VEGF

Vascular endothelial growth factor

VHL

von Hippel-Lindau

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Copyright information

© Springer-Verlag London 2012

Authors and Affiliations

  1. 1.Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of ChinaShanghai Jiao Tong University School of MedicineShanghaiChina

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