The Journal of Experimental Medicine
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Published 18 January 2005. doi:10.1084/jem.20041535
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 2, 221-231
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ARTICLE

 Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors

Stephen L. Nutt, Donald Metcalf, Angela D'Amico, Matthew Polli, and Li Wu

The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia

CORRESPONDENCE Stephen L. Nutt: nutt{at}wehi.edu.au or Li Wu: wu{at}wehi.edu.au

PU.1 is an Ets family transcription factor that is essential for fetal liver hematopoiesis. We have generated a PU.1gfp reporter strain that allowed us to examine the expression of PU.1 in all hematopoietic cell lineages and their early progenitors. Within the bone marrow progenitor compartment, PU.1 is highly expressed in the hematopoietic stem cell, the common lymphoid progenitor, and a proportion of common myeloid progenitors (CMPs). Based on Flt3 and PU.1 expression, the CMP could be divided into three subpopulations, Flt3+ PU.1hi, Flt3– PU.1hi, and Flt3– PU.1lo CMPs. Colony-forming assays and in vivo lineage reconstitution demonstrated that the Flt3+ PU.1hi and Flt3– PU.1hi CMPs were efficient precursors for granulocyte/macrophage progenitors (GMPs), whereas the Flt3– PU.1lo CMPs were highly enriched for committed megakaryocyte/erythrocyte progenitors (MEPs). CMPs have been shown to rapidly differentiate into GMPs and MEPs in vitro. Interestingly, short-term culture revealed that the Flt3+ PU.1hi and Flt3– PU.1hi CMPs rapidly became CD16/32high (reminiscent of GMPs) in culture, whereas the Flt3– PU.1lo CMPs were the immediate precursors of the MEP. Thus, down-regulation of PU.1 expression in the CMP is the first molecularly identified event associated with the restriction of differentiation to erythroid and megakaryocyte lineages.

Abbreviations used: AML, acute myeloid leukemia; cDC, conventional DC; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; ES, embryonic stem; GMP, granulocyte/macrophage progenitor; HSC, hematopoietic stem cell; IRES, internal ribosome entry site; Meg, megakaryocyte; MEP, megakaryocyte/erythrocyte progenitor; pDC, plasmacytoid DC; SCF, stem cell factor; TN, triple negative.


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