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Proto-Oncogenes and the Lymphomyeloid Bridge in Normal T-Cell Development
Ellen V. Rothenberg1, Boyoung Shin1, Jihyun Irizarry1, Samantha Chang1, Wen Zhou1,2
1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125 USA;
2Present address: BillionToOne, Menlo Park, CA
The textbook view of hematopoietic development features a central split between progenitors of lymphocytes and progenitors giving rise to everything else. At the molecular level, and in terms of intrinsic developmental potential, however, there is a strong connection between the early precursors in the T cell lineage and pathways leading to granulocyte, macrophage, and dendritic cell fates. This T-myeloid connection is preserved from the bone marrow into the thymus, where developing T cell precursors continue to be able to generate myeloid cells for multiple cell divisions even after encountering the strong Notch pathway signals in the thymic environment. A molecular explanation for this connection is that the cells retain significant expression of the myeloid-promoting transcription factor PU.1 for multiple cell cycles after they enter the thymus, only silencing it during commitment to the T-cell fate. However, recent data show that the cells do not simply navigate a choice between a myeloid fate and a T-cell fate. Along with PU.1, the early T cell precursors (ETPs) also naturally express a provocative combination of regulatory genes that are not expressed by more advanced T lineage cells, but are highly associated with acute T-cell leukemias: Lmo2, Lyl1, Hhex, Mef2c, and Erg, among others. Previous work from others has suggested that the genes encoding these factors have minimal or no roles within normal T cell development, even though they can cause malignant transformation in gain of function experiments. However, the methods used to test loss of function of these genes were not able to interrogate the stages when these genes are normally most active. In this talk, we present new evidence that most of these proto-oncogenic factors as well as PU.1 indeed play active roles in normal early T-cell precursors, controlling the timing of the switch between self-renewal in a progenitor state and T lineage differentiation. These factors each govern distinct sets of target genes in the early T cell precursors to restrain T-cell progression at different steps. The normal T cell program thus emerges not only from a lymphomyeloid precursor state but also through a gauntlet of potentially oncogenic regulatory activities that are finally shut down before T-cell receptor expression.
Support was from NIH grants HD100039 and AI151704 to EVR. BS was supported by an Irvington Postdoctoral Fellowship from the Cancer Research Institute and a Baxter Fellowship from Caltech.