Supplementary Figure 7: Revised model of the hematopoietic hierarchy with an early bifurcation of distinct myeloid lineage pathways.

(a) The classical model with initial segregation of myeloid/Mk/E and lymphoid potential via a CMP and CLP, with a common CMP-derived GMP that gives rise to all monocyte-macrophage and granulocyte lineages. (b) Model incorporating the LMPP, where lymphoid and megakaryocyte-erythroid potentials separate early, but both the LMPP and CMP produce the same GMP with combined potential for all monocyte-macrophage and granulocyte lineages. (c) Model supported by the work described herein based on an early branching point generating LMPPs and erythroid-megakaryocyte primed multi-potent progenitor (EMkMPP), where the monocyte-macrophage and granulocyte lineages separate along with the lymphoid and megakaryocyte/erythroid potentials, according to their Gata1 expression, generating progenitors restricted to eosinophil-mast cell (and likely basophil) fate (EoMP), or to neutrophil or monocyte-macrophage fate (preNM, NMP). The GATA-1 and Flt3 expression domains are indicated. It should be noted that there is no direct evidence yet that the Flt3⁻ fraction of preNMs derive from multi-potent progenitors (MPPs), so this pathways remains hypothetical. (d) Composite model of the work described herein that includes a CMP placed upstream of both the EMkMPP and the preNM, assuming it contains all monocyte-macrophage and granulocyte potentials at the single cell level, something yet to be determined. For all models it should be noted that other commitment pathways are possible, given the lineage potentials of the progenitors involved. For example, direct commitment of MPPs or another multi-potent progenitor to an Mk-E fate, circumventing the CMP and/or EMkMPP cannot be ruled out. In addition, these models do not incorporate all established findings in the hematopoietic hierarchy, such as the sustained myeloid programming of CLPs and downstream lymphoid progenitors.