Figure 3.

PU.1 and Notch collectively determine T vs. myeloid lineage fates. (A) Notch signaling within the thymus normally constrains PU.1 effects to support early pro-T cell development while blocking alternative fates that PU.1 would otherwise promote. Notch signaling itself does not repress PU.1 expression; however, other transcription factors induced by Notch signaling eventually silence expression of Spi1 during the DN2b stage. (B) Separation of the effects of PU.1 within the T-cell pathway from effects of PU.1 to promote lineage deviation, in PU.1 gain of function experiments. A fraction of cells expressing high levels of PU.1 shift to a myeloid-like state that can be phenotypically distinguished from cells remaining within the T-cell state. This distinction is necessary to relate gain-of-function effects of PU.1 in pro-T cells to effects of loss of endogenous PU.1 in perturbation experiments. Lineage deviation is associated with a broad loss of Notch signal response in the cells, suggesting that the constraint mechanism shown in A has been overwhelmed in these cells. Biochemical mechanisms of these effects remain to be fully defined. Schematic in A, adapted from (58); in B, adapted from (85).