Transcription factors have been shown to play an important role in the tight control and for fine-tuning of lineage decisions that take place during the development of the various different cell types present in blood. Interestingly, certain factors appear to be essential for genetic programming of specific lineages, and in the absence of such factors, lineage promiscuity has been observed. We have now derived a novel mouse model system to further address the role of specific myeloid transcription factors during hematopoeisis and to determine their essential functions during macrophage specification. Interestingly, in vitro differentiation of cells derived from these animals gives rise to terminally differentiated, functional macrophage cultures with sustained self-renewing activity. Preliminary results show that in addition to myeloid-specific markers, such macrophages can upregulate some B-cell specific genes in response to M-CSF withdrawal. Whereas lymphoid to myeloid reprogramming has been well documented, the reverse has not been achieved. Here we will analyse whether macrophage to B-cell reprogramming is also possible and outline a novel experimental system to test this hypothesis both in vitro and in vivo. Knowledge gained from these experiments will add strength to a growing body of evidence supporting the role of specific transcription factors in the control of lineage reprogramming and plasticity.