Downregulation of Signal Transducer and Activator of Transcription 5 (STAT5) in CD34+ Cells Promotes Megakaryocytic Development, Whereas Activation of STAT5 Drives Erythropoiesis

Abstract

Although it has been proposed that the common myeloid progenitor gives rise to granulocyte/monocyte progenitors and megakaryocyte/erythroid progenitors (MEP), little is known about molecular switches that determine whether MEPs develop into either erythrocytes or megakaryocytes. We used the thrombopoietin receptor c-Mpl, as well as the megakaryocytic marker CD41, to optimize progenitor sorting procedures to further subfractionate the MEP (CD34

Mathematical modeling reveals differential effects of erythropoietin on proliferation and lineage commitment of human hematopoietic progenitors in early erythroid culture

“…At the time of isolation, CD34 + cells from human PBMNC, are 85% CD34 + CD38 + IL3Ra − CD45RA − CD90 − CD45lo ( Figure 1A), previously defined as CMP 27,28 and 15% of CD34 + cells are CD34 + CD45lo IL − 3Rlo CD38 + CD90 − CD45RA + , GMP as previously described, 29,30 which do not persist in erythroid culture (Online Supplementary Figure S1). CD34 + cells cultured in serum-free medium supplemented with appropriate cytokines including SCF, IL-3 and epo mature into erythroid cells.…”

Tight Control of STAT5 Activity Determines Human CD34-Derived Interstitial Dendritic Cell and Langerhans Cell Development

“…Signal transducer and activator of transcription 5 (STAT5) plays an important role in hematopoiesis, regulating self-renewal, proliferation, and lineage decisions of hematopoietic stem cells and hematopoietic progenitor cells (HPC) (12)(13)(14)(15)(16). Most myeloid cells express cytokine receptors that are able to induce STAT5 activation, and STAT5 has been shown to regulate the development of various myeloid lineages (13,17).…”

Aberrant signal transduction pathways in myeloproliferative neoplasms

“…Depletion of STAT5 from CD34( þ ) cells in the presence of Tpo and stem cell factor favors megakaryocytic differentiation at the expense of erythroid differentiation. 91 Overexpression of an activated form of STAT5 impaired megakaryocyte development favoring erythroid differentiation at the expense of megakaryocyte differentiation. 91 Thus, at low levels of expression, JAK2 V617F might only activate STAT3, which might suffice for platelet formation.…”

“…91 Overexpression of an activated form of STAT5 impaired megakaryocyte development favoring erythroid differentiation at the expense of megakaryocyte differentiation. 91 Thus, at low levels of expression, JAK2 V617F might only activate STAT3, which might suffice for platelet formation. At higher expression levels, coupling to both TpoR and EpoR will lead to STAT5 activation, and this would favor the erythroid program.…”