Low HOX gene expression in PML-RAR-positive leukemia results from suppressed histone demethylation
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F18%3A10375344" target="_blank" >RIV/00216208:11130/18:10375344 - isvavai.cz</a>
Alternative codes found
RIV/68378050:_____/18:00495591 RIV/00064203:_____/18:10375344
Result on the web
<a href="https://doi.org/10.1080/15592294.2017.1413517" target="_blank" >https://doi.org/10.1080/15592294.2017.1413517</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1080/15592294.2017.1413517" target="_blank" >10.1080/15592294.2017.1413517</a>
Alternative languages
Result language
angličtina
Original language name
Low HOX gene expression in PML-RAR-positive leukemia results from suppressed histone demethylation
Original language description
Homeobox (HOX) genes are frequently dysregulated in leukemia. Previous studies have shown that aberrant HOX gene expression accompanies leukemogenesis and affects disease progression and leukemia patient survival. Patients with acute myeloid leukemia (AML) bearing PML-RAR fusion gene have distinct HOX gene signature in comparison to other subtypes of AML patients, although the mechanism of transcription regulation is not completely understood. We previously found an association between the mRNA levels of HOX genes and those of the histone demethylases JMJD3 and UTX in PML-RAR- positive leukemia patients. Here, we demonstrate that the release of the PML-RAR-mediated block in PML-RAR-positive myeloid leukemia cells increased both JMJD3 and HOX gene expression, while inhibition of JMJD3 using the specific inhibitor GSK-J4 reversed the effect. This effect was driven specifically through PML-RAR fusion protein since expression changes did not occur in cells with mutated RAR and was independent of differentiation. We confirmed that gene expression levels were inversely correlated with alterations in H3K27me3 histone marks localized at HOX gene promoters. Furthermore, data from chromatin immunoprecipitation followed by sequencing broaden a list of clustered HOX genes regulated by JMJD3 in PML-RAR-positive leukemic cells. Interestingly, the combination of GSK-J4 and all-trans retinoic acid (ATRA) significantly increased PML-RAR-positive cell apoptosis compared with ATRA treatment alone. This effect was also observed in ATRA-resistant NB4 clones, which may provide a new therapeutic opportunity for patients with acute promyelocytic leukemia (APL) resistant to current treatment. The results of our study reveal the mechanism of HOX gene expression regulation and contribute to our understanding of APL pathogenesis.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
—
Continuities
S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2018
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Epigenetics
ISSN
1559-2294
e-ISSN
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Volume of the periodical
13
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
73-84
UT code for WoS article
000426913700008
EID of the result in the Scopus database
2-s2.0-85041521050