Extrinsic signals determine myeloid-erythroid lineage switch in MN1 leukemia.
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.


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.
Heuser
Michael
M
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Park
Gyeongsin
G
Moon
Yeonsook
Y
Berg
Tobias
T
Xiang
Ping
P
Kuchenbauer
Florian
F
Vollett
Sarah
S
Lai
Courteney
C
Humphries
R Keith
RK
D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D041905:Erythroid Cells / Q000378:metabolism / Q000473:pathology*; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D015534:Trans-Activators; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
D007377:Interleukin-3; D015850:Interleukin-6; D008565:Membrane Proteins; C501081:Mn1 protein, mouse; D015513:Oncogene Proteins; D019089:Stem Cell Factor; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C084881:flt3 ligand protein; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3