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

Journal of Hematology & Oncology

Julia Starkova⁵  Jan Trka²  Jan Stary⁶  Marry M van den Heuvel-Eibrink¹  Harry A Drabkin⁴  Maarten Fornerod³  Marketa Zaliova⁵  Katerina Rejlova⁵  Ester Mejstrikova²  Karel Fiser⁵  Karolina Skvarova Kramarzova⁵ 

[1] Department of Pediatric Oncology and Hematology, ErasmusMC-Sophia Childrens Hospital, Rotterdam, The Netherlands;CLIP–Childhood Leukaemia Investigation Prague, Department of Paediatric Hematology and Oncology, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic;Department of Biochemistry, ErasmusMC, Rotterdam, The Netherlands;Department of Hematology and Oncology, Medical University of South Carolina, Charleston, SC, USA;CLIP–Childhood Leukaemia Investigation Prague, Department of Paediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University Prague, Prague, Czech Republic;Department of Paediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University Prague and University Hospital Motol, Prague, Czech Republic

关键词: Epigenetic modifiers;    Myelopoiesis;    Homeobox genes;    Acute myeloid leukemia;   

Others  :  1133477
DOI  :  10.1186/s13045-014-0094-0

 received in 2014-09-18, accepted in 2014-12-04,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Skvarova Kramarzova et al.; licensee BioMed Central.

【 图 表 】

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