Fes Tyrosine Kinase Promotes Survival and Terminal Granulocyte Differentiation of Factor-dependent Myeloid Progenitors (32D) and Activates Lineage-specific Transcription Factors

Abstract

The c-fps/fes proto-oncogene encodes a 92-kDa protein-tyrosine kinase that is involved in myeloid cell development and function. We have recently shown that expression of an activated allele of Fes (Fes act ) in monocyte precursors resulted in their differentiation into functional macrophages through the activation of lineage-specific transcription factors. We now report that this kinase also plays a role in the survival and terminal differentiation of granulocyte progenitors. The expression of Fes act in factor-dependent 32D cells prevented their apoptotic death after interleukin-3 removal, but Fes act -expressing cells remained factor-dependent for proliferation. Removal of interleukin-3 from the Fes actexpressing cells was followed by granulocytic differentiation in the absence of granulocyte colony-stimulating factor within 4 -8 days. The differentiated cells had distinctive granulocyte morphology and there was up-regulation of CD11b, Gr-1, and late differentiation markers such as lactoferrin, suggesting that this kinase induced terminal granulocytic differentiation. Concomitantly, Fes act down-regulated the macrophage marker F4/80, suggesting that the biological activity of Fes was coordinated in a lineage-specific manner. Further analysis showed that Fes act caused activation of CCAAT/enhancer-binding protein-␣ and STAT3, two transcription factors that are involved in granulocyte differentiation. Our results provide evidence that Fes may be a key component of the granulocyte differentiation machinery, and suggest a potential mechanism by which this kinase may regulate granulocyte-specific gene expression.

Spatial and Temporal Changes in the Subcellular Localization of the Nuclear Protein–Tyrosine Kinase, c-Fes

“…Differentiation of the promyelocytic cell line, HL-60, is blocked by antisense oligonucleotides to c-fes (Ferrari et al, 1990;Manfredini et al, 1997). Overexpression of normal c-Fes or activated forms induces differentiation of myeloid leukemia cell lines K562 (Yu et al, 1989), U937 (Kim and Feldman, 2002), and 32D (Kim et al, 2003). Transcription factors that are essential for myeloid cell differentiation are activated by cFes (Borellini et al, 1991;Kim et al, 2004).…”

Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype

“…Markers for late stages of myeloid differentiation, Gr-1 and integrin M (CD11b) surface antigens (26,27), were used to assess maturational status of the EV, WT, and MT cells. Consistent with morphological differences (Fig.…”

New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes

“…53 FES may be a key component of the granulocyte differentiation machinery and contributes to lineage determination at the level of multilineage hematopoietic progenitors as well as the more committed granulo-monocytic progenitors. 54 Another gene that may be involved in myeloid differentiation is MNDA, encoding the myeloid cell nuclear differentiation antigen. 55 It is expressed exclusively in maturing myeloid cells and cell lines, and is not expressed in lymphoid cells.…”