Abstract
Hematopoiesis is a complex process regulated by both cell intrinsic and cell extrinsic factors. Alterations in the expression of critical genes during hematopoiesis can modify the balance between stem cell differentiation and proliferation, and may ultimately give rise to leukemia and other diseases. AF10 is a transcription factor that has been implicated in the development of leukemia following chromosomal rearrangements between the AF10 gene and one of at least two other genes, MLL and CALM. The link between AF10 and leukemia, together with the known interactions between AF10 and hematopoietic regulators, suggests that AF10 may be important in hematopoiesis and in leukemic transformation. Here we show that AF10 is important for proper hematopoietic differentiation. The induction of hematopoietic differentiation in both human hematopoietic cell lines and murine total bone marrow cells triggers a decrease of AF10 mRNA and protein levels, particularly in stem cells and multipotent progenitors. Gain- and loss-of-function studies demonstrate that over- or under-expression of AF10 leads to apoptotic cell death in stem cells and multipotent progenitors. We conclude that AF10 plays a key role in the maintenance of multipotent hematopoietic cells.
Highlights
In adult vertebrates, hematopoiesis takes place in the bone marrow starting with the integration of signals originated by cells located in the hematopoietic stem cell (HSC) environment, known as the HSC niche
The in vitro assays developed in the human hematopoietic cell lines HEL, K562, CMK and HL60 showed a reduction of both AF10 protein and mRNA levels during the progression of cell differentiation (Figure 1-S3), suggesting an in vivo down regulation of AF10 in the later stages of hematopoiesis
A detailed analysis of these results revealed that the four cell lines used in this work, expressed different basal AF10 levels before differentiation
Summary
Hematopoiesis takes place in the bone marrow starting with the integration of signals originated by cells located in the hematopoietic stem cell (HSC) environment, known as the HSC niche. AF10 was recently shown to be present in a complex containing Tcf4/bcatenin and Dot1L in mouse small intestinal crypts, zebrafish, and Drosophila, where it participates in the maintenance of intestinal cell homeostasis [31,32] These data, together with the fact that AF10 interacts with other proteins implicated in the hematopoietic differentiation and its involvement in leukemic transformation [16,17], suggest that AF10 has an important role in the regulation of cell proliferation and differentiation in several tissues. Mouse bone marrow-derived immature hematopoietic cells show high AF10 expression levels, whereas these levels are very low in differentiated macrophages, recapitulating our observations in immortalized cell lines Taken together, these data support the conclusion that AF10 plays an important role in the early stages of hematopoiesis but not in differentiated stages. These results provide insight into AF10 function during hematopoiesis and contribute to a better understanding of its role in leukemic transformation
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