In Vitro Differentiation of Tumor- Associated Macrophages from Monocyte Precursors with Modi<ed Melanoma-Conditioned Medium.

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Tumor-associated macrophages (TAMs) are one of most important components of the tumor microenvironment. Although many assays have been developed to differentiate monocytes into macrophages (Mϕ) for studying the biology of TAMs in vitro, little is known whether the macrophages induced by these approaches can recapitulate the biology of TAMs present in the tumor microenvironment. We have developed a novel assay to differentiate human monocytes into TAMs using modified melanoma-conditioned medium, which is derived from the concentrated tumor cell culture medium. Characterization of these modified melanoma-conditioned medium-induced macrophages (MCMI-Mϕ) by multiple flow cytometry, Luminex, microarray, and immunohistochemistry analyses indicates that MCMI-Mϕ are phenotypically and functionally highly similar to the TAMs present in the tumor microenvironment.






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Russel E. Kaufman

Professor Emeritus of Medicine

The overall focus of this laboratory has been the study of the genetic regulation of normal and leukemic hematopoietic cells. Hematopoietic stem cells are produced during embryonic and fetal development and migrate to fetal liver, spleen, thymus, and bone marrow to populate those organs for the "definitive" stages of hematopoiesis.

We initially cloned the genes that compose the beta globin gene locus and also characterized other genomic elements that reside in and help control the expression of the locus, including the discovery of L1 repeats.  We later identified specific regulatory elements that when mutated change the expression of the locus, resulting in persistent expression of fetal globins into adulthood.  Our description of mutations in globin genes also explained an unusual form of thalassemia.
Our focus shifted to the identification and characterization of genes that control hematopoiesis, especially the human c-kit gene, normally expressed on erythroid progenitors. We identified important regulatory elements in the gene and how it interacted with other hematopoietic transcription factors. Later we identified the ets transcription factors as mediators of its signaling pathway and isolated a novel ets transcription factor, designated PE-2/ERF. Finally, we characterized the human GATA-1 and GATA-2 gene regulatory elements and demonstrated that signaling through the Kit signal transduction pathway has direct effects on these genes, showing that Kit signal transduction in setting up the erythroid developmental program.

This laboratory also has isolated the gene encoding the T cell specific gene CD7, expressed in T cell progenitors. During the characterization of the regulation of this gene, we identified a novel gene, SECTM1, that is closely linked physically and is the ligand for CD7. SECTM1 plays a role in regulating the immune response as well as other biological functions, and this is our current focus.
Key Words: Hematopoiesis, c-kit, ets, erythropoiesis, leukemia, gene regulation

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