The cleavage product ΔPML–RARα contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells

Jing, Yongkui; Xia, Lijuan; Lü, Min; Waxman, Samuel

doi:10.1038/sj.onc.1206568

Cited by 15 publications

(15 citation statements)

References 50 publications

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“…Finally, Western blot analyses of PML-RARa following MC2392 treatment showed rapid degradation of PML-RARa in NB4 cells (Fig. 1F) as has been reported for ATRA (36,37). Taken together the results show that MC2392 acts as a weak retinoid when compared with ATRA implying that it binds to RARa, activates RARa signaling, as well as induces the degradation of PML-RARa (Fig.…”

Section: Mc2392 Inhibits Hdac Activity Of the Pml-rara Complex And Masupporting

confidence: 56%

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

et al. 2014

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HDAC inhibitors (HDACi) are widely used in the clinic to sensitize tumorigenic cells for treatment with other anticancer compounds. The major drawback of HDACi is the broad inhibition of the plethora of HDAC-containing complexes. In acute promyelocytic leukemia (APL), repression by the PML-RARa oncofusion protein is mediated by an HDAC-containing complex that can be dissociated by pharmacologic doses of all trans retinoic acid (ATRA) inducing differentiation and cell death at the expense of side effects and recurrence. We hypothesized that the context-specific close physical proximity of a retinoid and HDACi-binding protein in the repressive PML-RARa-HDAC complex may permit selective targeting by a hybrid molecule of ATRA with a 2-aminoanilide tail of the HDAC inhibitor MS-275, yielding MC2392. We show that MC2392 elicits weak ATRA and essentially no HDACi activity in vitro or in vivo. Genome-wide epigenetic analyses revealed that in NB4 cells expressing PML-RARa, MC2392 induces changes in H3 acetylation at a small subset of PML-RARa-binding sites. RNA-seq reveals that MC2392 alters expression of a number of stress-responsive and apoptotic genes. Concordantly, MC2392 induced rapid and massive, caspase-8-dependent cell death accompanied by RIP1 induction and ROS production. Solid and leukemic tumors are not affected by MC2392, but expression of PML-RARa conveys efficient MC2392-induced cell death. Our data suggest a model in which MC2392 binds to the RARa moiety and selectively inhibits the HDACs resident in the repressive complex responsible for the transcriptional impairment in APLs. Our findings provide proof-of-principle of the concept of a context-dependent targeted therapy. Cancer Res; 74(8); 2328-39. Ó2014 AACR.

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Section: Mc2392 Inhibits Hdac Activity Of the Pml-rara Complex And Masupporting

confidence: 56%

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

et al. 2014

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“…As reported previously, ATRA induced the expression of RARα in the whole cell extract [22] and co-exposure with selenite had no additional effects (Figure 5A). The expression pattern was similar in the nuclear extract, except for that the combined treatment resulted in higher expression of RARα compared to ATRA alone.…”

Section: Resultssupporting

confidence: 85%

Selenite promotes all-trans retinoic acid-induced maturation of acute promyelocytic leukemia cells

et al. 2016

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Selective targeting of the PML/RARα oncoprotein demonstrates a successful molecular targeted therapy in acute promyelocytic leukemia (APL) with a typical t(15:17) chromosomal translocation. The zinc-thiolate coordination is critical for structural stability of zinc finger proteins, including the PML moiety of PML/RARα. Based on the known interaction of redox-active selenium compounds with thiolate ligands of zinc, we herein have investigated the abrogatory effects of selenite alone or in combination with all-trans retinoic acid on PML/RARα and the possible effects on differentiation in these cells. At pharmacological concentrations, selenite inhibited the proliferation and survival of APL originated NB4 cells. In combination with ATRA, it potentiated the differentiation of NB4 cells without any differentiating effects of its own as a single agent. Concordant with our hypothesis, PML/RARα oncoprotein expression was completely abrogated by selenite. Increased expression of RAR, PU.1 and FOXO3A transcription factors in the combined treatment suggested the plausible basis for increased differentiation in these cells. We show that selenite at clinically achievable dose targets PML/RARα oncoprotein for degradation and potentiates differentiation of promyelocytic leukemic cells in combination with ATRA. The present investigation reveals the hitherto unknown potential of selenite in targeted abrogation of PML/RARα in APL cells with prospective therapeutic value.

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“…9,57,58 Following PML-RAR␣ cleavage, PML protein has been shown to form many NBs with a number of proteins. 59 One well-studied NB is PML-eIF4E, which has been observed in several leukemic lines, including U937, K562, and ATRA-treated NB4, and is able to regulate mRNA export of certain growth-stimulatory proteins, specifically, cyclin D1.…”

Section: Atra-induced Posttranscriptional Suppression During Initiatimentioning

confidence: 99%

Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia

Harris

Özpolat

Abdi

et al. 2004

Blood

114

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All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation, and apoptosis in cancer cells, including acute promyelocytic leukemia (APL). In APL, expression of promyelocytic leukemia protein retinoic acid receptor-␣ (PML-RAR␣) fusion protein, owing to the t(15; 17) reciprocal translocation, leads to a block in the promyelocytic stage of differentiation. Here, we studied molecular mechanisms involved in ATRA-induced growth inhibition and myeloid cell differentiation in APL. By employing comprehensive high-throughput proteomic methods of 2-dimensional (2-D) gel electrophoresis and amino acid-coded mass tagging coupled with electrospray ionization (ESI) mass spectrometry, we systematically identified a total of 59 differentially expressed proteins that were consistently modulated in response to ATRA treatment. The data revealed significant downregulation of eukaryotic initiation and elongation factors, initiation factor 2 (IF2), eukaryotic initiation factor 4AI (eIF4AI), eIF4G, eIF5, eIF6, eukaryotic elongation factor 1A-1 (eEF1A-1), EF-1-␦, eEF1␥, 14-3-3⑀, and 14-3-3/␦ (P < .05). The translational inhibitor DAP5/p97/NAT1 (deathassociated protein 5) and PML isoform-1 were found to be up-regulated (P < .05). Additionally, the down-regulation of heterogeneous nuclear ribonucleoproteins (hnRNPs) C1/C2, UP2, K, and F; small nuclear RNPs (snRNPs) D3 and E; nucleoprotein tumor potentiating region (TPR); and protein phosphatase 2A (PP2A) were found (P < .05); these were found to function in pre-mRNA processing, splicing, and export events. Importantly, these pro-

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The cleavage product ΔPML–RARα contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells

Cited by 15 publications

References 50 publications

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

Context-Selective Death of Acute Myeloid Leukemia Cells Triggered by the Novel Hybrid Retinoid-HDAC Inhibitor MC2392

Selenite promotes all-trans retinoic acid-induced maturation of acute promyelocytic leukemia cells

Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia

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