SYNERGISTIC UP-REGULATION OF THE MYELOID-SPECIFIC PROMOTER FOR THE MACROPHAGE-COLONY-STIMULATING FACTOR-RECEPTOR BY AML1 AND THE T(8-21) FUSION PROTEIN MAY CONTRIBUTE TO LEUKEMOGENESIS

Citation
Kl. Rhoades et al., SYNERGISTIC UP-REGULATION OF THE MYELOID-SPECIFIC PROMOTER FOR THE MACROPHAGE-COLONY-STIMULATING FACTOR-RECEPTOR BY AML1 AND THE T(8-21) FUSION PROTEIN MAY CONTRIBUTE TO LEUKEMOGENESIS, Proceedings of the National Academy of Sciences of the United Statesof America, 93(21), 1996, pp. 11895-11900
Citations number
60
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
93
Issue
21
Year of publication
1996
Pages
11895 - 11900
Database
ISI
SICI code
0027-8424(1996)93:21<11895:SUOTMP>2.0.ZU;2-M
Abstract
AML1 is involved in the (8;21) translocation, associated with acute my elogenous leukemia (AML)-type M2, which results in the production of t he AML1-ETO fusion protein: the amino-terminal 177 amino acids of AML1 and the carboxyl-terminal 575 amino acids of ETO. The mechanism by wh ich AML1-ETO accomplishes leukemic transformation is unknown; however, AML1-ETO interferes with AML1 transactivation of such AML1 targets as the T-cell receptor beta enhancer and the granulocyte-macrophage colo ny-stimulating factor promoter. Herein, we explored the effect of AML1 -ETO on regulation of a myeloid-specific AML1 target, the macrophage c olony-stimulating factor (M-CSF) receptor promoter. We found that AML1 -ETO and AML1 network synergistically to transactivate the M-CSF recep tor promoter, thus exhibiting a different activity than previously des cribed. Truncation mutants within the ETO portion of AML1-ETO revealed the region of ETO necessary for the cooperativity between AML1 and AM L1-ETO lies between amino acids 347 and 540. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient wit h AML-M2 t(8;21) and the promonocytic cell line U937. Kasumi-1 cells e xhibited a significantly higher level of M-CSF receptor expression tha n U937 cells. Bone marrow from patients with AML-M2 t(8;21) also exhib ited a higher level of expression of M-CSF receptor compared with norm al controls. The upregulation of NI-CSF receptor expression by AML1-ET O may contribute to the development of a leukemic state in these patie nts.