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[Cancer Research 61, 2-7, January 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Histone Deacetylase-targeted Treatment Restores Retinoic Acid Signaling and Differentiation in Acute Myeloid Leukemia1

Fabiana F. Ferrara2, Francesco Fazi2, Andrea Bianchini, Fabrizio Padula, Vania Gelmetti, Saverio Minucci, Marco Mancini, Pier Giuseppe Pelicci, Francesco Lo Coco and Clara Nervi3

Departments of Histology and Medical Embryology [F. F. F., F. F., A. B., F. P., C. N.] and Cellular Biotechnology and Hematology [M. M., F. L. C.], University of Rome "La Sapienza," 00161 Rome; Institute of Internal Medicine and Oncological Sciences, 06100 Perugia [V. G.]; European Institute of Oncology, Department of Experimental Oncology, 20141 Milan [S. M., P. G. P.], Italy

Histone deacetylase (HDAC)-dependent transcriptional repression of the retinoic acid (RA)-signaling pathway underlies the differentiation block of acute promyelocytic leukemia. RA treatment relieves transcriptional repression and triggers differentiation of acute promyelocytic leukemia blasts, leading to disease remission. We report that transcriptional repression of RA signaling is a common mechanism in acute myeloid leukemias (AMLs). HDAC inhibitors restored RA-dependent transcriptional activation and triggered terminal differentiation of primary blasts from 23 AML patients. Accordingly, we show that AML1/ETO, the commonest AML-associated fusion protein, is an HDAC-dependent repressor of RA signaling. These findings relate alteration of the RA pathway to myeloid leukemogenesis and underscore the potential of transcriptional/differentiation therapy in AML.




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