Schuster, Mikkel B6; Frank, Anne-Katrine6; Bagger, Frederik O7; Rapin, Nicolas7; Vikesaa, Jonas8; Porse, Bo T6
1 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet2 The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet3 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet4 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet5 Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet6 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet7 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet8 Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
Acute myeloid leukemia (AML) develops via a multistep process involving several genetic and epigenetic events, which ultimately leads to the formation of a heterogeneous population of malignant cells, of which only a small subpopulation termed the leukemia initiating cell (LIC) is able to sustain the leukemia. The identity of the LIC is highly diverse and ranges from populations resembling hematopoietic stem cells or multipotent progenitors (MPPs) to more committed myeloid progenitors, and the question still remains whether this is a direct consequence of which cells are targets of the final transforming events. In this study, we use premalignant cells from a Cebpa mutant AML model, in which the LIC population resembles granulocyte-macrophage progenitors (GMPs), to show that premalignant GMPs undergo spontaneous immortalization with a high clonal frequency when cultured in vitro, suggesting that these cells constitute the target of the final transforming events. Furthermore, we show that premalignant GMPs are characterized by a distinct T cell gene expression signature correlating with an increased potential for differentiation toward the T cell lineage. These findings have implications for our understanding of the transcriptional wiring in premalignant myeloid progenitors and how this contributes to the development of AML.
Experimental Hematology, 2013, Vol 41, Issue 10, p. 882-893