Molecular mechanisms involved in commitment to the lymphoid lineage
We have found that common lymphocyte progenitors (CLP) in the mouse bone marrow maintain a latent myeloid developmental potential when stimulated through ectopic hIL-2Rβ receptors. Early thymocyte progenitors (ProT cells) also retain this latent myeloid developmental potential. Granulocyte/macrophage colonies arising from hIL-2Rβ transgenic ProT cells have initiated TCRβ gene rearrangement, a lymphoid specific event. The presence of TCRβ gene rearrangement illustrates that the ProT cells were truly diverted from the lymphoid to myeloid lineage induced by signaling through the ectopic cytokine receptor. The lymphoid to myeloid lineage switch is mediated through downregulation of the master B cell regulator Pax5 (BSAP). We show that Pax5 is downregulated by signaling through ectopic hIL-2Rβ as well as enforced expression of C/EBPα, two situations where lymphoid progenitors are diverted to the myeloid lineage. In addition, enforced expression of Pax5 in CLP blocks lineage conversion following IL-2 stimulation and restricts cells to the B cell lineage. These results indicate that hematopoietic cells are more plastic in their developmental potential than is currently thought.