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
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
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.