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RARalpha 1/RARalpha 2-PML mRNA Expression in Acute Promyelocytic Leukemia Cells: A Molecular and Laboratory-Clinical Correlative Study

Yun-Ping Li, Janet Andersen, Arthur Zelent, Sreenivas Rao, Elisabeth Paietta, Martin S. Tallman, Peter H. Wiernik, and Robert E. Gallagher

From the Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY; the Dana Farber Cancer Institute, Boston, MA; the Northwestern University Medical School, Chicago, IL; and the Leukaemia Research Fund, London, UK.

In addition to the major fusion gene PML-RARalpha , the t(15; 17) in acute promyelocytic leukemia (APL) produces the reciprocal fusion gene RARalpha -PML. To determine the scope of RARalpha -containing mRNA expression in APL cells, we tested PML-RARalpha -positive APL cells for the presence of mRNAs initiated from two distinct RARalpha gene promoters, alpha 1 and alpha 2. From the normal allele, both RARalpha 1 and RARalpha 2 mRNAs were expressed in all APL cases (N = 24). From the translocated allele, RARalpha 1-PML mRNA was expressed in 77% and RARalpha 2-PML mRNA in 28% of cases (N = 98). RARalpha 2-PML mRNA was not observed in the absence of RARalpha 1-PML mRNA. There was no association between RARalpha 1-PML or RARalpha 2-PML mRNA expression and the type of PML-RARalpha mRNA formed by either 5' or 3' breaksites in the PML gene. RARalpha 1-PML mRNAs and RARalpha 2-PML mRNAs from 5' PML breaksite cases coded for full-length RARalpha -PML proteins but RARalpha 2-PML mRNAs from 3' PML breaksite cases encoded a truncated RARalpha 2 peptide. RARalpha 1/alpha 2-PML mRNA expression was not associated with differences in APL cell sensitivity to all-trans retinoic acid(tRA)-induced differentiation in vitro or in clinical outcome after tRA or chemotherapy induction therapy (protocol E2491). Our analysis indicated that RARalpha 1/alpha 2-PML mRNA expression markedly differs from normal RARalpha 1/alpha 2 mRNA expression, that the difference in RARalpha 1-PML and RARalpha 2-PML mRNA expression frequency is primarily related to the genomic separation of the RARalpha 1 and RARalpha 2 coding exons, and that variations in RARalpha 1/alpha 2-PML mRNA expression likely have no clinically relevant function in APL cells.

Blood, Vol. 90 No. 1 (July 1), 1997: pp. 306-312
© 1997 by The American Society of Hematology.


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