RARα-PLZF overcomes PLZF-mediated repression of
            <i>CRABPI</i>
            , contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia

Guidez, Fabien; Parks, Sarah; Wong, Henna; Jovanović, Jelena; Mays, Ashley; Gilkes, Amanda F.; Mills, Ken I.; Guillemin, Marie Claude; Hobbs, Robin M.; Pandolfi, Pier Paolo; Solomon, Ellen; Grimwade, David

doi:10.1073/pnas.0704433104

Cited by 63 publications

(55 citation statements)

References 62 publications

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“…The t(11;17) APL is mostly of poor prognosis, and the disease is relatively RA-resistant, possibly due to RA-resistant corepressor recruitment (33) and/or CRABPI derepression (16). Additionally, the inhibition of C/EBPe by PLZF-RARα (34) and the inhibition of C/EBPα by RARα-PLZF reported here, both required for terminal granulocytic differentiation, unequivocally contribute to this RA resistance and support the use of HDAC inhibitors for the treatment of t(11;17) APL.…”

Section: Discussionmentioning

confidence: 99%

“…At the molecular level, RARα-PLZF binds to DNA via the PLZF binding site and derepresses PLZF target genes such as cyclin A, Hoxb2a and c-Myc (13)(14)(15), thereby causing increased proliferation. In addition, RA resistance has been associated with an up-regulation of cellular retinoic acid binding protein 1 (CRABPI) (16), although additional mechanisms could also contribute to this resistance. Furthermore, how RARα-PLZF modifies the tumor phenotype remains to be clarified.…”

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confidence: 99%

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RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Girard

Tremblay

Humbert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.APL | granulocyte differentiation | transcription inhibition | histone modification | protein interaction

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Girard

Tremblay

Humbert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Several studies (19,20) on PLZF-RARA revealed that the PLZF moiety recruits corepressors and polycomb group proteins in an ATRA-insensitive manner and directly deregulates PLZF target genes to induce leukemia. In addition, reciprocal RARA-PLZF fusion protein also contributes to leukemogenesis (21,22). However, the molecular basis for induction of aberrant self-renewal capacity by PLZF-RARA is unclear.…”

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confidence: 99%

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

Ono

Masuya

Ishii

et al. 2017

Molecular and Cellular Biology

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PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the PLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying PLZF-mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with Plzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by Plzf and PLZF-

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“…cited therein). The RARA, PLZF and BCR genes are known to be involved in translocations generating fusion proteins that play a critical role in leukemogenesis (6). A number of BAC clones mapped to five known common fragile sites (CFS) were also used.…”

Section: Introductionmentioning

confidence: 99%

The importance of molecular cytogenetic analysis prior to using cell lines in research: The case of the KG-1a leukemia cell line

2012

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Abstract. KG-1 and its less differentiated subline KG-1a are leukemia cell lines used in research in a number of laboratories. The karyotypes of the two lines were initially identical. In the following years, further analysis revealed that the cell lines had acquired additional karyotypical abnormalities and differed in the presence of certain typical chromosomal rearrangements. To obtain cytogenetic authentication prior to the use of the two cell lines, we analyzed their karyotype by combining DAPI-and CMA-chromosome bandings and a fluorescence in situ hybridization (FISH)-based approach by using BAC clones useful for the identification of chromosome regions of interest. Sequences of the MYC, PLZF, RARA and BCR genes, that are known to play a critical role in leukemogenesis, and certain BAC clones mapped to five known common fragile sites (CFS) were used for the FISH analysis. A telomeric probe (TTAGGG)n and a set of BAC clones were used to characterize the marker chromosome der(1) that was observed in the cell line KG-1a. The existence of notable differences between the karyotype of the KG-1a cell line previously described, and that described in this study, demonstrate that the use of established cancer cell lines should be preceded by cytogenetic and/ or molecular characterization. IntroductionKG-1 and KG-1a leukemia cell lines have been used in research in numerous laboratories. KG-1, a cell line established in 1978 by Koeffler and Golde (1), was derived from the bone marrow of a male individual with erythroleukemia that developed into acute myeloid leukemia (AML). The KG-1 cells are mostly at the myeloblast or promyelocyte stage of maturation.KG-1a is a less differentiated subline of KG-1 developed after 35 passages. The karyotypes of the two lines were initially identical (2). The comparative karyotypic analysis of the two cell lines performed in subsequent years by other authors using various cytogenetic and molecular techniques (3,4) revealed that the cell lines had acquired additional karyotypical abnormalities and, although sharing several identical structural aberrations, differed in the presence of certain typical chromosomal rearrangements. Particularly, Mrózek et al (4) used G-banding, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses to produce a detailed description of chromosome aberrations in the KG-1 and KG-1a cell lines. Comparative analysis of the two karyotypes is extremely useful for authentication of the two cell lines.To obtain a characterization and cytogenetic authentication of the two cell lines prior to use, their karyotype was analyzed by combining DAPI-and CMA-chromosome bandings and a FISH-based approach. For FISH analyses a number of BAC clones useful for the identification of chromosome regions of interest were employed, including the MYC, retinoic acid receptor (RARA), promyelocytic leukemia zinc finger (PLZF) and breakpoint cluster region (BCR) genes. Evidence suggests that the MYC copy number gain has a role in human myeloid leukemia (5 and ref...

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RARα-PLZF overcomes PLZF-mediated repression of CRABPI , contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia

Cited by 63 publications

References 62 publications

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

The importance of molecular cytogenetic analysis prior to using cell lines in research: The case of the KG-1a leukemia cell line

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