Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all‐trans retinoic acid

Abstract

Summary. Acute promyelocytic leukaemia (APL) with t(11;17)/PLZF-RARa responds poorly to all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ), in contrast to APL with t(15;17)/PML-RARa. Molecular studies have shown that histone deacetylase (HDAC) recruited by PLZF-RARa is associated with the ATRA resistance. Here, we analysed in vitro the differentiation of APL cells with t(11;17) using ATRA, As 2 0 3 , granulocyte colony-stimulating factor (G-CSF), HDAC inhibitor trichostatin A (TSA), or combinations of these. Although 1 mM ATRA, which stimulated the differentiation of APL cells with t(15;17), was insuf®cient to induce differentiation, 3 mM ATRA induced terminal differentiation into granulocytes. As 2 0 3 alone or in combination with ATRA induced neither differentiation nor apoptosis. However, the combination of TSA and 1 mM ATRA had a potent differentiating effect, although TSA alone had little effect. The combination of 1 mM ATRA and G-CSF did not induce differentiation. These results indicate that APL cells with t(11;17) need a higher concentration of ATRA than those with t(15;17) to differentiate and suggest that HDAC inhibitor is a promising differentiation enhancer in APL with t(11;17).

CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system

“…There are several cancerspecific rearrangements that have been shown recently to involve chromatin-remodeling genes. Acute promyelocytic leukemia (APL) results from translocations between the RARa gene on chromosome 17 and either the PML gene on chromosome 15 or the PLZF gene on chromosome 11 (Grignani et al, 1998;Lin et al, 1998;Kitamura et al, 2000). These chimeric transcription factors interact with the SAP histone deacetylase complex, and differences in these interactions may account for the different responses of APML with these two translocations to retinoid therapy.…”

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

“…It is plausible that the very low levels of PLZF/RARa remaining in the cell are su cient for transformation or that PLZF/RARa induces some irreversible events in the cell, for example at the chromatin level. Yet, these APL associated to the variant t(11;17) translocation are not completely insensitive to RA as very high doses of RA, or combining RA to GM-CSF or histone desacetylase inhibitors were shown to induce di erentiation in RAresistant t(11;17) associated APL (Jansen et al, 1999;Kitamura et al, 2000). We suggest that in these cases, PLZF/RARa degradation facilitated the response to other stimuli.…”

Transcriptional regulation in acute promyelocytic leukemia

“…The clinical e ectiveness of this regime was ®rst illustrated by the use of a HDAC inhibitor, phenylbutyrate, in combination with ATRA, to treat a relapsed case of t(15;17) APL at the Memorial Sloan-Kettering Cancer Center (Warrell et al, 1998). Subsequently, HDAC inhibitors plus ATRA have been shown to induce t(11;17) APL cell di erentiation in vitro, suggesting that these compounds may be used to treat the primary RA-resistant APL (Kitamura et al, 2000). To extend this concept of transcription therapy, two groups have recently shown that HDAC inhibitors, in combination with agents such as GM-CSF or ATRA, e ectively trigger apoptosis and cellular di erentiation of AML cells in vitro (Ferrara et al, 2001;Wang et al, 1999).…”