Comprehensive genomic screens identify a role for PLZF-RARα as a positive regulator of cell proliferation via direct regulation of c-MYC

Rice, Kim L.; Hormaeche, Itsaso; Doulatov, Sergei; Flatow, Jared; Grimwade, David; Mills, Ken I.; Leiva, Magdalena; Ablain, Julien; Ambardekar, Charuta; McConnell, Melanie J.; Dick, John E.; Licht, Jonathan D.

doi:10.1182/blood-2009-03-206524

Cited by 53 publications

(56 citation statements)

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“…2D and E). We also assessed expression of the cellcycle regulator CDKN1B (p27 KIP1 ), which has previously been shown to be induced in response to PLZF-RARa expression (20). We confirmed that PLZF-RARa increases CDKN1B mRNA levels, but vorinostat was observed to downregulate CDKN1B (Supplementary Fig.…”

Section: Ink4dsupporting

confidence: 66%

“…The PLZFRARb3 cell line is based on the U937T autoregulatory tetracycline-off system. Cells were cultured as previously described (20), and PLZF-RARa expression was induced by washing cells with PBS and culturing without tetracycline (Sigma). B412, PR9, and U937-A/E cells expressing PLZF-RARa, PML-RARa, or AML1-ETO, respectively, under the control of a Zn-inducible promoter, were obtained from Drs.…”

Section: Reagents and Cell Linesmentioning

confidence: 99%

“…To test the effects of LAFP expression on sensitivity to vorinostat-induced cell death, we used PLZFRARb3 cells, which are U937 cells stably transfected with PLZF-RARa cDNA under the control of a tetracycline-off system (20). When cultured in the absence of tetracycline, PLZFRARb3 cells express PLZF-RARa (Fig.…”

Section: Expression Of the Lafp Plzf-rara Enhances Sensitivity To Hdamentioning

confidence: 99%

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Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Petruccelli

Pettersson

Rincón

et al. 2013

Molecular Cancer Therapeutics

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Histone deacetylase inhibitors (HDI) show activity in a broad range of hematologic and solid malignancies, yet the percentage of patients in any given malignancy who experience a meaningful clinical response remains small. In this study, we sought to investigate HDI efficacy in acute myeloid leukemia (AML) cells expressing leukemia-associated fusion proteins (LAFP). HDIs have been shown to induce apoptosis, in part, through accumulation of DNA damage and inhibition of DNA repair. LAFPs have been correlated with a DNA repairdeficient phenotype, which may make them more sensitive to HDI-induced DNA damage. We found that expression of the LAFPs PLZF-RARa, PML-RARa, and RUNX1-ETO (AML1-ETO) increased sensitivity to DNA damage and apoptosis induced by the HDI vorinostat. The increase in apoptosis correlated with an enhanced downregulation of the prosurvival protein BCL2. Vorinostat also induced expression of the cell-cycle regulators p19INK4D and p21 WAF1 and triggered a G 2 -M cell cycle arrest to a greater extent in LAFP-expressing cells. The combination of LAFP and vorinostat further led to a greater downregulation of several base excision repair (BER) enzymes. These BER genes represent biomarker candidates for response to HDI-induced DNA damage. Notably, repair of vorinostat-induced DNA double-strand breaks was found to be impaired in PLZFRARa-expressing cells, suggesting a mechanism by which LAFP expression and HDI treatment cooperate to cause an accumulation of damaged DNA. These data support the continued study of HDI-based treatment regimens in LAFP-positive AMLs.

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Section: Ink4dsupporting

confidence: 66%

Section: Reagents and Cell Linesmentioning

confidence: 99%

Section: Expression Of the Lafp Plzf-rara Enhances Sensitivity To Hdamentioning

confidence: 99%

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Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Petruccelli

Pettersson

Rincón

et al. 2013

Molecular Cancer Therapeutics

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“…I n t h e c a s e o f t h e p o o r response to ATRA, on the other hand, the underlying mechanism has been hypothesized to be due to enhanced co-repressor activity conferred by the PLZF moiety of the PLZF-RARA fusion (Grignani et al, 1998;He et al, 1998;Lin et al, 1998). However, the notion that PLZF/RARA is irresponsive to ATRA stimulation has been contradicted in more recent studies demonstrating ATRA-induced gene expression and differentiation also in PLZF/RARA expressing APL cells (Nasr et al, 2008;Petti et al, 2002;Rice et al, 2009). Thus, further work is needed in order to fully understand the mechanism underlying the insensitivity of PLZF/RARA positive APL cells to ATRA.…”

Section: The Mechanism Of Apl Therapy Resistancementioning

confidence: 99%

Acute Promyelocytic Leukemia: A Model Disease for Targeted Cancer Therapy

Lång¹,

Bøe²

2011

Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

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“…7,8 AML1/ETO as well as PLZF/RARα have been found to induce the transcription factor c-MYC, 9,10 and ectopic expression of c-MYC in murine bone marrow elicited an aggressive myeloid leukemia by conferring self-renewal capacity to committed myeloid progenitor cells. 11,12 The Polycomb group (PcG) protein BMI1 is essential for the leukemic transformation property of PLZF/RARα and a target gene of c-MYC.…”

Section: Introductionmentioning

confidence: 99%

Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells

et al. 2012

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Comprehensive genomic screens identify a role for PLZF-RARα as a positive regulator of cell proliferation via direct regulation of c-MYC

Cited by 53 publications

References 50 publications

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Acute Promyelocytic Leukemia: A Model Disease for Targeted Cancer Therapy

Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells

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