Revisiting the differentiation paradigm in acute promyelocytic leukemia

Ablain, Julien

doi:10.1182/blood-2011-02-329367

Cited by 112 publications

(81 citation statements)

References 99 publications

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“…23,40 Our observations again uncouple differentiation from APL eradication and have important new implications for the underlying mechanisms. 10,14 First, they support the model that granulocytic differentiation can be achieved through transcriptional derepression of PML-RARA-HDAC-silenced genes. Indeed, differentiation can be achieved without any PML-RARA loss.…”

Section: Discussionmentioning

confidence: 64%

“…Conversely, in several models, VPA both enhances ATRA-induced PML-RARA degradation, LIC clearance and survival. Together with previous indications, 10,14 these new findings converge on a model whereby transcriptional repression of myeloid differentiation program by PML-RARA-bound HDAC controls differentiation, while PML-RARA abundance controls LIC self-renewal. Further studies should elucidate why PLZF/RARA degradation does not suffice to clear clonogenic properties of these cells, 13 and why the VPA and ATRA did not synergize for their clearance in this model.…”

Section: Discussionmentioning

confidence: 83%

“…13,15,39 These observations further strengthen the proposed link between LIC activity and PML-RARA loss. 10,14,39 VPA may synergize with ATRA for LIC clearance in vivo We then analyzed the effect of the combination of VPA and ATRA in vivo. Interestingly, when primary leukemias were pre-treated with VPA for 1 day, PML-RARA protein levels were reduced in ATRA plus VPA-treated mice compared with ATRA-treated ones (Figure 5a), though differentiation was essentially unaltered at 2 days of exposure to drugs (Figure 5b).…”

Section: Vpa Induces Tumor Regression and Apls Differentiation In Vivomentioning

confidence: 99%

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Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

et al. 2012

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Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 83%

Section: Vpa Induces Tumor Regression and Apls Differentiation In Vivomentioning

confidence: 99%

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Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

et al. 2012

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“…This evidence explains why leukemic blast differentiation without PML-RARA degradation, at least in this case, is not sufficient to eradicate the disease. This example clearly outlines the importance of targeting the right cellular subpopulation for disease eradication [40]. Studies aimed at unraveling the effects of epigenetic drugs on different hematopoietic subpopulations revealed a dual action of epigenetic agents, which is dependent on the developmental stage of the cell.…”

Section: The Importance Of Cscs In Epigenetic Therapymentioning

confidence: 99%

“…ATRA and arsenic trioxide, which are the most two important drugs for early diagnosed APL, both target the stability of PML-RARA: ATRA through the RARΑ moiety, and arsenic trioxide through the PML moiety [39]. A recent study has demonstrated that treatment of APL mice with low-dose ATRA for 3 days leads to the differentiation of leukemia cells, with a limited antitumor effect and overall survival rate, whereas high concentrations of ATRA lead to the loss of leukemia-initiating cells (LICs) and eradicate APL [40].…”

Section: Aml Oncofusion Proteins Trigger An Aberrant Epigenetic Landsmentioning

confidence: 99%

Epigenetic alterations in acute myeloid leukemias

2014

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Acute myeloid leukemia (AML) is a heterogeneous disease for which the standard treatment with cytotoxic chemotherapy has remained largely unchanged for over four decades, with unfavorable clinical results. Epigenetic alterations have been described in several AMLs, and in some cases their origin has been studied in detail mechanistically (such as in acute promyelocytic leukemia, caused by the promyelocytic leukemia-retinoic acid receptor-a fusion protein). Recently, the advent of massive parallel sequencing has revealed that > 70% of AML cases have mutations in DNA methylation-related genes or mutations in histone modifiers, showing that epigenetic alterations are key players in the development of most, if not all, AMLs, and pointing to the exploitation of new molecular targets for more efficacious therapies. This review provides a brief overview of the latest findings on the characterization of the epigenetic landscape of AML and discusses the rationale for the optimization of epigenetic therapy of AML.

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Acute promyelocytic leukemia: A population‐based study on incidence and survival in the United States, 1975‐2008

Chen

Kantarjian

Wang

et al. 2012

Cancer

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BACKGROUND: With the introduction of all‐trans retinoic acid and arsenic trioxide, the management of acute promyelocytic leukemia (APL) has changed dramatically. We performed a population‐based study of APL in the United States to determine its incidence and relative survival (RS) during a 34‐year period. METHODS: We identified 1397 patients diagnosed with APL between 1975 and 2008 in the Surveillance, Epidemiology, and End Results database. Patients were categorized into 4 age groups and 3 calendar periods. As a comparison, we also reviewed the outcome of APL patients treated at our institution during approximately the same time interval. RESULTS: The incidences of APL increased with time period and patient age. Short‐ and long‐term RS improved with each calendar period, with the greatest improvement occurring between 1991 and 1999; 5‐year RS rates were 0.18 for patients diagnosed in 1975‐1990, 0.52 in 1991‐1999, and 0.64 in 2000‐2008. Age was an important predictor of survival. For example, the 5‐year RS rate in patients diagnosed in 2000‐2008 was 0.38 for patients aged ≥60 years and 0.73 and 0.75 for patients aged <20 years and 20‐39 years, respectively. Similar treads of improvements in the survival were observed in APL patients treated at our institution. CONCLUSIONS: The incidence of APL has increased, especially in the last decade. Clinical outcome improved remarkably in patients with APL diagnosed from 1991 to 1999, mainly because of the increased use of all‐trans retinoic acid. Cancer 2012;. © 2012 American Cancer Society.

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Revisiting the differentiation paradigm in acute promyelocytic leukemia

Cited by 112 publications

References 99 publications

Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

Epigenetic alterations in acute myeloid leukemias

Acute promyelocytic leukemia: A population‐based study on incidence and survival in the United States, 1975‐2008

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