Reduced c-Myb activity compromises HSCs and leads to a myeloproliferation with a novel stem cell basis.
Murine haematopoietic stem cells (HSCs) are contained in the Kit+Sca1+Lin(-) (KSL) population of bone marrow and are able to repopulate lethally irradiated mice. Myeloproliferative disorders (MPDs) are thought to be clonogenic diseases arising at the level of the HSC. Here, we show that mice expressing low levels of the transcription factor c-Myb, as the result of genetic knockdown, develop a transplantable myeloproliferative phenotype that closely resembles the human disease essential thrombocythaemia (ET). Unlike wild-type cells, the KSL population in c-myb knockdown bone marrow cannot repopulate irradiated mice and does not transfer the disease. Instead, cells positive for Kit and expressing low to medium levels of CD11b acquire self-renewing stem cell properties and are responsible for the perpetuation of the myeloproliferative phenotype.
College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, UK. p.garcia@bham.ac.uk or
Paloma
P
García
Mary
M
Clarke
Alexandros
A
Vegiopoulos
Oscar
O
Berlanga
Ana
A
Camelo
Maelle
M
Lorvellec
Jon
J
Frampton
D000818:Animals; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000502:physiology*; D013920:Thrombocythemia, Essential / Q000473:pathology*
D020598:Proto-Oncogene Proteins c-myb