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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1477-1481
RAPID COMMUNICATION
Constitutive Degradation of PML/RAR Through the Proteasome Pathway
Mediates Retinoic Acid Resistance
Mirco Fanelli,
Saverio Minucci,
Vania Gelmetti,
Clara Nervi,
Carlo Gambacorti-Passerini, and
Pier Giuseppe Pelicci
From the European Institute of Oncology, the Department of
Experimental Oncology, Milan; Istituto Nazionale Tumori, Divisione
Oncologia Sperimentale D, Milan; Istituto di Clinica Medica I,
University of Perugia, Perugia; and Universita' `La Sapienza,"
Istituto di Istologia, Rome, Italy.
PML/RAR is the leukemogenetic protein of acute
promyelocytic leukemia (APL). Treatment with retinoic acid (RA) induces
degradation of PML/RAR, differentiation of leukaemic blasts, and
disease remission. However, RA resistance arises during RA treatment of APL patients. To investigate the phenomenon of RA resistance in APL, we
generated RA-resistant sublines from APL-derived NB4 cells. The
NB4.007/6 RA-resistant subline does not express the PML/RAR protein,
although its mRNA is detectable at levels comparable to those of the
parental cell line. In vitro degradation assays showed that the
half-life of PML/RAR is less than 30 minutes in NB4.007/6 and longer
than 3 hours in NB4. Treatment of NB4.007/6 cells with the proteasome
inhibitors LLnL and lactacystin partially restored
PML/RAR protein expression and resulted in a partial release of the
RA-resistant phenotype. Similarly, forced expression of PML/RAR, but
not RAR, into the NB4/007.6 cells restored sensitivity to RA
treatment to levels comparable to those of the NB4 cells. These results
indicate that constitutive degradation of PML/RAR protein may lead
to RA resistance and that PML/RAR expression is crucial to convey RA
sensitivity to APL cells.
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