Abstract
All-trans retinoic acid (ATRA) is well established as differentiation therapy for acute promyelocytic leukemia (APL) in which the PML–RARα (promyelocytic leukemia-retinoic acid receptor α) fusion protein causes blockade of the retinoic acid (RA) pathway; however, in types of acute myeloid leukemia (AML) other than APL, the mechanism of RA pathway inactivation is not fully understood. This study revealed the potential mechanism of high ATRA sensitivity of mixed-lineage leukemia (MLL)-AF9-positive AML compared with MLL-AF4/5q31-positive AML. Treatment with ATRA induced significant myeloid differentiation accompanied by upregulation of RARα, C/EBPα, C/EBPɛ and PU.1 in MLL-AF9-positive but not in MLL-AF4/5q31-positive cells. Combining ATRA with cytarabine had a synergistic antileukemic effect in MLL-AF9-positive cells in vitro. The level of dimethyl histone H3 lysine 4 (H3K4me2) in the RARα gene-promoter region, PU.1 upstream regulatory region (URE) and RUNX1+24/+25 intronic enhancer was higher in MLL-AF9-positive cells than in MLL-AF4-positive cells, and inhibiting lysine-specific demethylase 1, which acts as a histone demethylase inhibitor, reactivated ATRA sensitivity in MLL-AF4-positive cells. These findings suggest that the level of H3K4me2 in the RARα gene-promoter region, PU.1 URE and RUNX1 intronic enhancer is determined by the MLL-fusion partner. Our findings provide insight into the mechanisms of ATRA sensitivity in AML and novel treatment strategies for ATRA-resistant AML.
Highlights
Differentiation therapy using all-trans retinoic acid (ATRA) is well established for the treatment of acute promyelocytic leukemia (APL)[1,2] in which the PML–RARa fusion protein causes blockade of the retinoic acid (RA) pathway.[3,4] There has been significant success using ATRA to treat APL, but there has been little research into the use of ATRA in a non-APL acute myeloid leukemia (AML) setting
In terms of induction of myeloid differentiation in mixed-lineage leukemia (MLL)-rearranged AML, we have previously described that the demethylating agent 5-aza-2’deoxycitidine enhanced the sensitivity of MLL-AF9-expressing AML cells to ATRA,[8] and Iijima et al.[9] have reported that the combination of the histone deacetylase inhibitor trichostatin A and ATRA was effective as a growth inhibitor and differentiation enhancer in MLL-AF9-expressing leukemia cells
Niitsu et al.[21] demonstrated that ATRA sensitivity of MLL-rearranged AML cells were varied and that might be related to p16 expression level. These findings suggest that chromatin remodeling, such as histone modification by methylation or acetylation, is an important factor for ATRA sensitivity in MLL-rearranged AML, and the epigenetic priming of RA pathway is necessary for the differentiation therapy in MLL-rearranged AML
Summary
Differentiation therapy using all-trans retinoic acid (ATRA) is well established for the treatment of acute promyelocytic leukemia (APL)[1,2] in which the PML–RARa (promyelocytic leukemia-retinoic acid receptor a) fusion protein causes blockade of the retinoic acid (RA) pathway.[3,4] There has been significant success using ATRA to treat APL, but there has been little research into the use of ATRA in a non-APL acute myeloid leukemia (AML) setting. ATRA does not induce myeloid differentiation in non-APL AML cells. Myeloid differentiation is regulated via the activation of RARa gene by ATRA.[4,5] Studies of the molecular mechanism blocking differentiation in non-APL AML cells indicate that expression of RARa is diminished in non-APL AML cells and that its restoration can induce differentiation of human AML cells.[6,7] These observations suggest that a lack of RARa expression impairs the RA pathway in non-APL AML cells, blocking myeloid differentiation. These studies revealed that epigenetic mechanisms, including DNA methylation, histone methylation and acetylation, are involved in the repression of RARa expression in non-APL AML cells.[6,7] Based on these findings, recent studies have focused on the development of differentiation therapies for non-APL AML using ATRA combined with epigenetic modifiers.[8,9,10,11,12] Recently, it has been reported that inhibition of lysine-specific demethylase 1 (LSD1), which demethylates dimethyl histone 3 lysine 4 (H3K4me2) to silence expression of its target gene, reactivates the RA pathway in non-APL AML.[13,14]
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