ABSTRACT
Considerable effort has been expended to identify genes that account for myeloid lineage commitment and development. However, currently available non-invasive mouse models utilize myeloid-specific reporters that are significantly expressed in hematopoietic stem cells as well as lymphoid compartments. Here, we describe a myeloid-specific marker that is not shared by any other lineage. We show that lactotransferrin mRNA is expressed by Gr-1(+)/CD11b(+) cells in the bone marrow, as opposed to hematopoietic stem cells or any peripheral cell population. To follow the progeny of lactotransferrin-expressing bone marrow cells, we generated a mouse model in which a reporter gene is irreversibly activated from the lactotransferrin-promoter. We found that lactotransferrin-reporter labels a majority of neutrophils, monocytes, macrophages and distinct subtypes of dendritic cells, while excluding T, B, natural killer cells, interferon-producing killer dendritic cells, plasmacytoid dendritic cells, erythrocytes and eosinophils. Lactotransferrin-reporter(-) bone marrow cells retain lymphoid, erythroid and long-term repopulating potential, while lactotransferrin-reporter(+) bone marrow cells confer only myeloid, but not lymphoid potential. We conclude that lactotransferrin represents a late stage differentiation marker of neutrophils, macrophages and distinct subtypes of dendritic cells.
Subject(s)
Dendritic Cells/metabolism , Lactoferrin/genetics , Macrophages/metabolism , Monocytes/metabolism , Neutrophils/metabolism , Animals , CD11b Antigen/metabolism , Cell Tracking , Erythroid Cells/metabolism , Gene Expression , Gene Order , Genes, Reporter , Genetic Vectors/genetics , Lactoferrin/metabolism , Lymphocytes/metabolism , Mice , Mice, Transgenic , Myeloid Cells/metabolism , Organ Specificity/genetics , Promoter Regions, Genetic , RNA, Messenger/genetics , Receptors, Chemokine/metabolismABSTRACT
The large difference in phenotypes among tumour populations may stem from the stochastic origin of tumours from distinct cells - tumour cells are assumed to retain the phenotypes of the cells from which they derive. Yet, functional studies addressing the cellular origin of leukaemia are lacking. Here we show that the cells of origin of both, BCR/ABL-induced chronic myeloid (CML) and B-cell acute lymphoid leukaemia (B-ALL), resemble long-term haematopoietic stem cells (LT-HSCs). During disease-maintenance, CML LT-HSCs persist to function as cancer stem cells (CSCs) that maintain leukaemia and require signalling by the transcription factor STAT5. In contrast, B-ALL LT-HSCs differentiate into CSCs that correspond to pro-B cells. This transition step requires a transient IL-7 signal and is lost in IL-7Rα-deficient cells. Thus, in BCR/ABLp185(+) B-ALL and BCR/ABLp210(+) CML, the final phenotype of the tumour as well as the abundance of CSCs is dictated by diverging differentiation fates of their common cells of origin.
