Pro-proliferative function of the long isoform of PML-RARα involved in acute promyelocytic leukemia

Tussié-Luna, María Isabel; Rozo, Liliana; Roy, Ananda L.

doi:10.1038/sj.onc.1209388

Cited by 14 publications

(6 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although differences between the two major isoforms in biological activity and APL phenotypes are subtle, early case reports indicated that patients with PML-RARα(S) fusions had higher rate of relapse and shorter durations of remission and survival compared to patients with L isoforms [Huang et al, 1993; Jurcic et al, 2001; Vahdat et al, 1994]. In a later study, PML-RARα(L), but not PML-RARα(S), directly promoted cell growth by altering chromatin structure and thereby activating the growth-promoting gene c-fos in response to mitogen stimulation [Tussie-Luna et al, 2006]. …”

Section: Resultsmentioning

confidence: 99%

Promyelocytic leukemia nuclear bodies support a late step in DNA double‐strand break repair by homologous recombination

Yeung

Denissova

Nasello

et al. 2012

J of Cellular Biochemistry

View full text Add to dashboard Cite

SUMMARY The PML protein and PML nuclear bodies (PML-NB) are implicated in multiple cellular functions relevant to tumor suppression, including DNA damage response. In most cases of acute promyelocytic leukemia, the PML and retinoic acid receptor alpha (RARA) genes are translocated, resulting in expression of oncogenic PML-RARα fusion proteins. PML-NB fail to form normally, and promyelocytes remain in an undifferentiated, abnormally proliferative state. We examined the involvement of PML protein and PML-NB in homologous recombinational repair (HRR) of chromosomal DNA double-strand breaks. Transient overexpression of wild-type PML protein isoforms produced hugely enlarged or aggregated PML-NB and reduced HRR by ~2 fold, suggesting that HRR depends to some extent upon normal PML-NB structure. Knockdown of PML by RNA interference sharply attenuated formation of PML-NB and reduced HRR by up to 20 fold. However, PML-knockdown cells showed apparently normal induction of H2AX phosphorylation and RAD51 foci after DNA damage by ionizing radiation. These findings indicate that early steps in HRR, including recognition of DNA double-strand breaks, initial processing of ends, and assembly of single-stranded DNA/RAD51 nucleoprotein filaments, do not depend upon PML-NB. The HRR deficit in PML-depleted cells thus reflects inhibition of later steps in the repair pathway. Expression of PML-RARα fusion proteins disrupted PML-NB structure and reduced HRR by up to 10 fold, raising the possibility that defective HRR and resulting genomic instability may figure in the pathogenesis, progression and relapse of acute promyelocytic leukemia.

show abstract

Section: Resultsmentioning

confidence: 99%

Promyelocytic leukemia nuclear bodies support a late step in DNA double‐strand break repair by homologous recombination

Yeung

Denissova

Nasello

et al. 2012

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…17 It is still possible that persistent PML-RAR␣ expression may have indirect effects on gene expression; for example, a recent study revealed that the Fos gene is activated by PML-RAR␣ as a consequence of an alteration in the chromatin structure near the Fos gene, making it more accessible to transactivation by other transcription factors. 33 The activation of Fos expression in APL cells may ) qRT-PCR analysis of Fos, Jun, Egr-1, Tnf, and Vcam1 expression levels was performed using primers specific for each cDNA. All data were normalized to Gapdh, since the expression of this gene does not change during myeloid differentiation ( Figure 5C).…”

Section: Discussionmentioning

confidence: 99%

Commonly dysregulated genes in murine APL cells

Yuan

Payton

Holt³

et al. 2006

Blood

View full text Add to dashboard Cite

To identify genes that are commonly dysregulated in a murine model of acute promyelocytic leukemia (APL), we first defined gene expression patterns during normal murine myeloid development; serial gene expression profiling studies were performed with primary murine hematopoietic progenitors that were induced to undergo myeloid maturation in vitro with G-CSF. Many genes were reproducibly expressed in restricted developmental "windows," suggesting a structured hierarchy of expression that is relevant for the induction of developmental fates and/or differentiated cell functions. We compared the normal myeloid developmental transcriptome with that of APL cells derived from mice expressing PML-RAR␣ under control of the murine cathepsin G locus. While many promyelocytespecific genes were highly expressed in all APL samples, 116 genes were reproducibly dysregulated in many independent APL samples, including Fos, Jun, Egr1, Tnf, and Vcam1. However, this set of commonly dysregulated genes was expressed normally in preleukemic, early myeloid cells from the same mouse model, suggesting that dysregulation occurs as a "downstream" event during disease progression. These studies suggest that the genetic events that lead to APL progression may converge on common pathways that are important for leukemia pathogenesis. (Blood. 2007;109: 961-970)

show abstract

“…11,12 In mouse models, PML-RAR␣ induces a disease similar to acute promyelocytic leukemia (APL). 13,14 Microarray analyses elucidated several leukemogenic mechanisms and pathways.…”

Section: Introductionmentioning

confidence: 99%

Chromatin modifications induced by PML-RARα repress critical targets in leukemogenesis as analyzed by ChIP-Chip

Hoemme

Zada²,

Behre³

et al. 2008

Blood

View full text Add to dashboard Cite

IntroductionBalanced translocations that lead to expression of aberrant fusion proteins are a hallmark of acute leukemias. 1 Many of these fusion proteins function as aberrant transcription factors that are an initiating event in leukemogenesis. 2 Some translocations, eg those involving the MLL gene can lead to phenotypically diverse forms of leukemia, whereas the t(15;17) uniformly leads to acute promyelocytic leukemia. The reasons why some translocations are leukemia-type specific, whereas others are not, is unknown.Histone modifications such as methylation of histone H3 at lysine 4 and 9 and acetylation of histone H3 are closely linked to the transcriptional activation status. In t(15;17), the chimeric PML-RAR␣ fusion protein has been shown to recruit corepressors such as DAXX, histone deacetylase (HDAC) activity, DNA methyltransferase activity, and the SUV39H1 histone methyltransferase to RAR␤2, the most extensively studied target gene. [3][4][5][6][7] PML-RAR␣ also interacts with histone deacetylase 1. 8 PML-RAR␣ homodimerization has been shown to relax the relatively stringent RAR␣ DNA binding specificity. 9,10 This gain of function is supposed to lead to many additional genomic binding sites that are not well defined. As a consequence, virtually all direct genomic targets of PML-RAR␣ are currently unknown. In addition, on a global level, the mechanistic alterations occurring at PML-RAR␣ target genes remain to be clarified.On a phenotypic level, the PML-RAR␣ fusion protein blocks differentiation and apoptosis and enhances self-renewal. 11,12 In mouse models, PML-RAR␣ induces a disease similar to acute promyelocytic leukemia (APL). 13,14 Microarray analyses elucidated several leukemogenic mechanisms and pathways. [15][16][17][18][19] For example, PML-RAR␣ induces activation of the Wnt signaling pathway. 17 Also, PML-RAR␣ alters the apoptotic response and expression of differentiation genes. 15 However, these studies do not distinguish between direct and indirect effects on gene expression. This knowledge is crucial to understand the mechanistic implications of PML-RAR␣ and to elucidate the reasons for the unique phenotype that is associated with its activities.The possibilities to understand transcription factor functions has recently been significantly improved by genome-wide approaches that identify target genes in vivo using Chromatin immunoprecipitation (ChIP)-Chip approaches. 20,21 In addition, the ability to use this method to map epigenetic modifications such as histone acetylation at promoters known to bind the transcription factor allows for the identification of the functional consequences of transcription factor binding to its genomic targets. 22,23 Using ChIP-chip analyses, we identified 372 direct PML-RAR␣ genomic targets and show that PML-RAR␣ induces heterochromatin formation on virtually all of its identified target genes. Several of the identified genes are known tumor suppressors and for one of the novel genes (S100P), we show a potential role in the PML-RAR␣-associated block in differenti...

show abstract

Pro-proliferative function of the long isoform of PML-RARα involved in acute promyelocytic leukemia

Cited by 14 publications

References 57 publications

Promyelocytic leukemia nuclear bodies support a late step in DNA double‐strand break repair by homologous recombination

Promyelocytic leukemia nuclear bodies support a late step in DNA double‐strand break repair by homologous recombination

Commonly dysregulated genes in murine APL cells

Chromatin modifications induced by PML-RARα repress critical targets in leukemogenesis as analyzed by ChIP-Chip

Contact Info

Product

Resources

About