Extrinsic signals determine myeloid-erythroid lineage switch in MN1 leukemia

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.

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.

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.

Our findings underscore the importance of microenvironmental signals for lineage choice in leukemia and identify signals that are important in myeloid-erythroid lineage decisions.