Extrinsic signals determine myeloid-erythroid lineage switch in MN1 leukemia
Received 29 December 2009; received in revised form 29 December 2009; accepted 6 January 2010. published online 21 January 2010.
Objective
Transcriptional control of hematopoietic lineage fate relies on the integration of many intra- and extracellular signals. To test whether the microenvironment impacts on leukemic phenotype, we exploited the MN1 model of acute myeloid leukemia under defined genetically modified microenvironmental conditions.
Materials and Methods
The requirement of both FLT3 and c-Kit signaling for MN1 leukemias was investigated using retroviral infection of bone marrow cells from wild-type, c-Kit–mutated (W41), and Flt3-ligand knockout cells, and bone marrow transplantation into wild-type, c-Kit–mutated, or Flt3-ligand knockout mice.
Results
Genetic disruption of both FLT3 and c-Kit signaling in the MN1-leukemia model was dispensable for MN1-induced leukemogenesis. However, it induced a switch from myeloid to erythroid phenotype that was preserved, when FLT3 signaling was restored by secondary transplantation of leukemic cells into wild-type recipients.
Conclusions
Our findings underscore the importance of microenvironmental signals for lineage choice in leukemia and identify signals that are important in myeloid-erythroid lineage decisions.
aTerry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
bDepartment of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
cDepartment of Laboratory Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada
dDepartment of Medicine, University of British Columbia, Vancouver, BC, Canada
Offprint requests to: R. Keith Humphries, M.D., Ph.D., Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada
ABSTRACT