Abstract
The AML1/ETO fusion protein found in acute myeloid leukemias functions as a transcriptional regulator by recruiting co-repressor complexes to its DNA binding site. In order to extend the understanding of its role in preleukemia, we expressed AML1/ETO in a murine immortalized pluripotent hematopoietic stem/progenitor cell line, EML C1, and found that genes involved in functions such as cell-to-cell adhesion and cell motility were among the most significantly regulated as determined by RNA sequencing. In functional assays, AML1/ETO-expressing cells showed a decrease in adhesion to stromal cells, an increase of cell migration rate in vitro, and displayed an impairment in homing and engraftment in vivo upon transplantation into recipient mice. Our results suggest that AML1/ETO expression determines a more mobile and less adherent phenotype in preleukemic cells, therefore altering the interaction with the hematopoietic niche, potentially leading to the migration across the bone marrow barrier and to disease progression.
Highlights
In order to study AML1/ETO’s role in preleukemia, we exploited a murine immortalized pluripotent hematopoietic stem/progenitor (HSPC) cell line, EML C1, which can be induced to differentiate into both the lymphoid and myeloid lineages upon appropriate cytokine treatment[14]
The analysis of gene expression by RNA sequencing showed that cell migration and cell-to-cell adhesion were among the most important functions regulated by the fusion protein, suggesting that interaction with the microenvironment may be altered in preleukemic precursors expressing the fusion protein
These results indicate that AML1/ETO regulates the expression of genes involved in migration and cell-to-cell adhesion in HSPC, and that these functions are altered in different acute myeloid leukemia (AML) subtypes suggesting they may be of relevance for disease progression
Summary
In order to study AML1/ETO’s role in preleukemia, we exploited a murine immortalized pluripotent hematopoietic stem/progenitor (HSPC) cell line, EML C1 (referred to as EML from here on), which can be induced to differentiate into both the lymphoid and myeloid lineages upon appropriate cytokine treatment[14]. Two AML1/ ETO-expressing EML clones were generated by retroviral transduction and characterized for their growth and differentiation properties. The analysis of gene expression by RNA sequencing showed that cell migration and cell-to-cell adhesion were among the most important functions regulated by the fusion protein, suggesting that interaction with the microenvironment may be altered in preleukemic precursors expressing the fusion protein This manuscript explores the effects of AML1/ETO expression on migration and adhesion properties in hematopoietic cells in vitro and homing/engraftment in vivo
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