The truncated RUNX1/ETO activates VLA-4-dependent adhesion and migration of hematopoietic progenitor cells

Ponnusamy, Kanagaraju; Chen-Wichmann, Linping; Kuvardina, Olga N.; Lausen, Jörn; Henschler, Reinhard; Wichmann, Christian

doi:10.3324/haematol.2014.106088

Cited by 9 publications

(16 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PSLG-1 repression results in an impediment of cellular adhesion, which was restored after depletion of AML1/ETO. Furthermore, the AML1/ETO9a splice variant was shown to influence adhesion and migration of hemopoietic progenitor cells via the regulation of VLA-4 expression 12 . This confirms that the deregulation of adhesion molecules and of migratory properties is an important feature of t(8; 21) + AML.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, genes encoding for proteins involved in cellular adhesion and/or migration were found to be common targets for the AML1, AML2 and AML3 transcription factors 9 , and aberrant expression of adhesion molecules has been described in acute lymphoblastic leukemia cases carrying the TEL/AML1 (or ETV6/RUNX1) fusion gene 10 . Moreover, expression of CD44 11 , VLA-4 12 and LFA-1(or CD11a) 13 adhesion molecules has been found to be directly regulated by AML1/ETO.…”

mentioning

confidence: 98%

See 1 more Smart Citation

AML1/ETO accelerates cell migration and impairs cell-to-cell adhesion and homing of hematopoietic stem/progenitor cells

Saia

Termanini

Rizzi

et al. 2016

Sci Rep

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

AML1/ETO accelerates cell migration and impairs cell-to-cell adhesion and homing of hematopoietic stem/progenitor cells

Saia

Termanini

Rizzi

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…19 Peptide-mediated interruption of RE tetramerization was performed using the NHR2-inhibitor peptide described before. 37 Efficacy of the shRNA against the RE breakpoint sequences was recently demonstrated.…”

Section: Methodsmentioning

confidence: 99%

RUNX1/ETO blocks selectin-mediated adhesion via epigenetic silencing of PSGL-1

et al. 2015

View full text Add to dashboard Cite

RUNX1/ETO (RE), the t(8;21)-derived leukemic transcription factor associated with acute myeloid leukemia (AML) development, deregulates genes involved in differentiation, self-renewal and proliferation. In addition, these cells show differences in cellular adhesion behavior whose molecular basis is not well understood. Here, we demonstrate that RE epigenetically silences the gene encoding P-Selectin Glycoprotein Ligand-1 (PSGL-1) and downregulates PSGL-1 expression in human CD34+ and murine lin− hematopoietic progenitor cells. Levels of PSGL-1 inversely and dose-dependently correlate with RE oncogene levels. However, a DNA-binding defective mutant fails to downregulate PSGL-1. We show by ChIP experiments that the PSGL-1 promoter is a direct target of RE and binding is accompanied by high levels of the repressive chromatin mark histone H3K27me3. In t(8;21)+ Kasumi-1 cells, PSGL-1 expression is completely restored at both the mRNA and cell surface protein levels following RE downregulation with short hairpin RNA (shRNA) or RE inhibition with tetramerization-blocking peptides, and at the promoter H3K27me3 is replaced by the activating chromatin mark H3K9ac as well as by RNA polymerase II. Upregulation of PSGL-1 restores the binding of cells to P- and E-selectin and re-establishes myeloid-specific cellular adhesion while it fails to bind to lymphocyte-specific L-selectin. Overall, our data suggest that the RE oncoprotein epigenetically represses PSGL-1 via binding to its promoter region and thus affects the adhesive behavior of t(8;21)+ AML cells.

show abstract

“…A number of these studies have identified an important role for RUNX1 in regulating cell adhesion and migration programs (Lie et al, ; Michaud et al, ; Wotton et al, ). Furthermore, RUNX1 regulation of several genes encoding cell adhesion molecules has been reported, including VLA‐4 (also known as α4β1; Ponnusamy et al, ), CD44 (Peterson et al, ), ITGAL (Puig‐Kroger et al, ), and PSGL1 (Ponnusamy et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, RUNX1 regulation of several genes encoding cell adhesion molecules has been reported, including VLA-4 (also known as α4β1; Ponnusamy et al, 2014), CD44 (Peterson et al, 2007), ITGAL (Puig-Kroger et al, 2003), and PSGL1 (Ponnusamy et al, 2015).…”

mentioning

confidence: 99%

Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells

Phillips

Taberlay

Woodworth

et al. 2017

Journal Cellular Physiology

View full text Add to dashboard Cite

Integrins are transmembrane adhesion receptors that play an important role in hematopoiesis by facilitating interactions between hematopoietic cells and extracellular matrix components of the bone marrow and hematopoietic tissues. These interactions are important in regulating the function, proliferation, and differentiation of hematopoietic cells, as well as their homing and mobilization in the bone marrow. Not surprisingly altered expression and function of integrins plays a key role in the development and progression of cancer including leukemias. However, the regulation of integrin gene expression is not well characterized and the mechanisms by which integrin genes are disrupted in cancer remain unclear. Here we demonstrate for the first time that a key regulator of hematopoiesis, RUNX1, binds to and regulates the promoters of both the ITGA6 and ITGB4 genes in myeloid cells. The ITGA6 and ITGB4 integrin genes form the α6β4 integrin receptor. However, our data indicate that RUNX1 functions differently at these two promoters. RUNX1 regulates ITGA6 through a consensus RUNX1 binding motif in its promoter. In contrast, although the ITGB4 promoter is also activated by RUNX1, it does so in the absence of a recognized consensus RUNX1 binding motif. Furthermore, our data suggest that regulation of ITGB4 may involve interactions between the promoter and upstream regulatory elements.

show abstract

The truncated RUNX1/ETO activates VLA-4-dependent adhesion and migration of hematopoietic progenitor cells

Cited by 9 publications

References 12 publications

AML1/ETO accelerates cell migration and impairs cell-to-cell adhesion and homing of hematopoietic stem/progenitor cells

AML1/ETO accelerates cell migration and impairs cell-to-cell adhesion and homing of hematopoietic stem/progenitor cells

RUNX1/ETO blocks selectin-mediated adhesion via epigenetic silencing of PSGL-1

Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells

Contact Info

Product

Resources

About