Haematologica
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Haematologica, Vol 90, Issue 12, 1607-1616
Copyright © 2005 by Ferrata Storti Foundation

Journal Article

Hypoxia-simulating agents and selective stimulation of arsenic trioxide-induced growth arrest and cell differentiation in acute promyelocytic leukemic cells

H Yan, ZG Peng, YL Wu, Y Jiang, Y Yu, Y Huang, YS Zhu, Q Zhao, and GQ Chen

Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao-Tong University (SJU-SM, formerly named Shanghai Second Medical University), Shanghai 200025, China.

BACKGROUND AND OBJECTIVES: We recently reported that hypoxia-mimetic agents cobalt chloride (CoCl2 CoCl2 ) and desferrioxamine (DFO) could induce differentiation of acute myeloid leukemic (AML) cells. Here, we investigate whether these two agents influence the in vitro differentiation-inducing effect of arsenic trioxide (As2O3) on AML cells, an effective drug for the treatment of acute promyelocytic leukemia (APL) that is a unique subtype of AML with a specific fusion protein, PML-RARalpha. DESIGN AND METHODS: The APL cell line NB4 and non-APL promonocytic leukemic cell line U937 were treated with As2O3 (0.5 microM) combined with CoCl2 (50 microM) or DFO (10 microM). The U937/PR9 subclone, whose expression of PML-RARalpha protein can be induced by Zn2+, was also investigated. Cellular differentiation was evaluated by morphological criteria and myeloid differentiation-related antigens and marker gene expression. The hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein were detected, respectively, by semi-quantitative/real-time quantitative reverse transcription polymerase chain reaction and immunoblots. PML-RARalpha protein was also analyzed. RESULTS: CoCl2 and DFO potentiated the growth-inhibiting and differentiation-inducing effects of low-dose As2O3, the latter enhancing CoCl2 and DFO-induced accumulation of HIF-1alpha protein in NB4 cells but not in U937 cells. These two hypoxia-mimetic agents also accelerated As2O3-induced modulation and degradation of PML-RARalpha protein in NB4 cells. Furthermore, inducible expression of the fusion gene restored the co-operative effects of As2O3 and CoCl2/DFO on U937/PR9 cells in terms of growth arrest, differentiation induction and HIF-1alpha protein accumulation. INTERPRETATION AND CONCLUSIONS: Mimicked hypoxia enhanced As2O3-induced differentiation, in which HIF-1alpha and PML/RARalpha proteins played an important role. These data provide new insights into the understanding of the mechanisms of the action of As2O3 in the treatment of patients with APL.


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W. Yuan, J. E. Payton, M. S. Holt, D. C. Link, M. A. Watson, J. F. DiPersio, and T. J. Ley
Commonly dysregulated genes in murine APL cells
Blood, February 1, 2007; 109(3): 961 - 970.
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