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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2014

Open Access 01-12-2014 | Research

Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations

Authors: Karolina Skvarova Kramarzova, Karel Fiser, Ester Mejstrikova, Katerina Rejlova, Marketa Zaliova, Maarten Fornerod, Harry A Drabkin, Marry M van den Heuvel-Eibrink, Jan Stary, Jan Trka, Julia Starkova

Published in: Journal of Hematology & Oncology | Issue 1/2014

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Abstract

Background

Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or rather represent the differentiation stage of the leukemic cell.

Method

To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells. These various stages of myeloid differentiation represent matched counterparts of morphological subgroups of AML. To further study the transcriptional alterations of HOX genes in hematopoiesis, we also analyzed gene expression of epigenetic modifiers in the subpopluations of healthy BM and leukemic cells.

Results

Unsupervised hierarchical clustering divided the AMLs into five clusters characterized by the presence of prevalent molecular genetic aberrations. Notably, the impact of genotype on HOX gene expression was significantly more pronounced than that of the differentiation stage of the blasts. This driving role of molecular aberrations was best exemplified by the repressive effect of the PML-RARa fusion gene on HOX gene expression, regardless of the presence of the FLT3/ITD mutation. Furthermore, HOX gene expression was positively correlated with mRNA levels of histone demethylases (JMJD3 and UTX) and negatively correlated with gene expression of DNA methyltranferases. No such relationships were observed in subpopulations of healthy BM cells.

Conclusion

Our results demonstrate that specific molecular genetic aberrations, rather than differentiation per se, underlie the observed differences in HOX gene expression in AML. Moreover, the observed correlations between epigenetic modifiers and HOX ex pression that are specific to malignant hematopoiesis, suggest their potential causal relationships.
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Metadata
Title
Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations
Authors
Karolina Skvarova Kramarzova
Karel Fiser
Ester Mejstrikova
Katerina Rejlova
Marketa Zaliova
Maarten Fornerod
Harry A Drabkin
Marry M van den Heuvel-Eibrink
Jan Stary
Jan Trka
Julia Starkova
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2014
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-014-0094-0

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