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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1496-1504
NEOPLASIA
Gene expression networks underlying retinoic acid-induced
differentiation of acute promyelocytic leukemia cells
Ting-Xi Liu,
Ji-Wang Zhang,
Jiong Tao,
Ruo-Bo Zhang,
Qing-Hua Zhang,
Chun-Jun Zhao,
Jian-Hua Tong,
Michel Lanotte,
Samuel Waxman,
Sai-Juan Chen,
Mao Mao,
Geng-Xi Hu,
Li Zhu, and
Zhu Chen
From the Shanghai Institute of Hematology,
Ruijin Hospital, Shanghai Second Medical University, the Institute of
Cell Biology, Chinese Academy of Sciences, and the Chinese National
Human Genome Center at Shanghai, Shanghai, China; Clontech
Laboratories, Palo Alto, CA; the Division of Neoplastic Diseases,
Department of Medicine, Mount Sinai Medical Center, New York, NY; and
Institute National de la Santé et de la Recherche Medicalé
(INSERM) Unité, Hospital Saint Louis, Paris, France.
To elucidate the molecular mechanism of
all-trans-retinoic acid (ATRA)-induced differentiation of
acute promyelocytic leukemia (APL) cells, the gene expression
patterns in the APL cell line NB4 before and after ATRA
treatment were analyzed using complementary DNA array,
suppression-subtractive hybridization, and
differential-display-polymerase chain reaction. A total of 169 genes,
including 8 novel ones, were modulated by ATRA. The ATRA-induced gene
expression profiles were in high accord with the
differentiation and proliferation status of the NB4 cells.
The time courses of their modulation were interesting. Among the 100 up-regulated genes, the induction of expression occurred most
frequently 12-48 hours after ATRA treatment, while 59 of 69 down-regulated genes found their expression suppressed within 8 hours.
The transcriptional regulation of 8 induced and 24 repressed
genes was not blocked by cycloheximide, which suggests that these
genes may be direct targets of the ATRA signaling pathway. A balanced
functional network seemed to emerge, and it formed the foundation of
decreased cellular proliferation, maintenance of cell
viability, increased protein modulation, and promotion of
granulocytic maturation. Several cytosolic signaling pathways,
including JAKs/STAT and MAPK, may also be implicated in the
symphony of differentiation.
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