Cell fusion involving progenitor cells is a newly recognized phenomenon thought to contribute to tissue differentiation. The molecular mechanisms governing cell fusion are unknown. P-glycoprotein and related ATP-binding cassette transporters are expressed by progenitor cells, but their physiological role in these cell types has not been defined. Here, we have cloned ABCB5, a rhodamine efflux transporter and novel member of the human P-glycoprotein family, which marks CD133-expressing progenitor cells among human epidermal melanocytes and determines as a regulator of membrane potential the propensity of this subpopulation to undergo cell fusion. Our findings show that polyploid ABCB5 ؉ cells are generated by cell fusion and that this process is specifically enhanced by ABCB5 Pglycoprotein blockade. Remarkably, multinucleated cell hybrids gave rise to mononucleated progeny, demonstrating that fusion contributes to culture growth and differentiation. Thus, our findings define a molecular mechanism for cell fusion involving progenitor cells and show that fusion and resultant growth and differentiation are not merely spontaneous events, but phenomena regulated by ABCB5 P-glycoprotein.Several recent reports have demonstrated that co-culture of pluripotent embryonic or mesenchymal stem cells with lineagecommitted cell types can give rise to cell hybrids as a result of cell fusion, and it has been shown that such cell hybrids can generate differentiated progeny in vitro and in vivo (1-5). These findings raise the possibility that cell fusion may represent a physiological mechanism by which endogenous progenitor cells participate in tissue plasticity and renewal. A cellular molecular marker identifying progenitor cells participating in cell fusion or associated with the regulation of cell fusion has as of yet not been identified, however. P-glycoproteins (P-gp) 1 and related members of the ABC superfamily of active transporters mediate multidrug resistance in mammalian cancers (6 -13) and serve physiologic transport (14 -21), differentiation (22, 23), and survival (24, 25) functions in nonmalignant cell types. Two known members of the ABC superfamily of transporters, ABCB1 (MDR1) P-gp and the ABCG2 (Bcrp1) transporter, are also expressed at high levels on stem and progenitor cell populations (26, 27), and the efflux capacity for the fluorescent dyes rhodamine-123 (28 -30) and Hoechst 33342 (31-34) mediated by these or related ABC transporters has been utilized for the isolation of such cell subsets. A physiologic role of ABC transporters in such progenitor cells has, however, not been defined. A recent study investigated a possible role of ABCB1 P-gp as a determinant of membrane fluidity and membrane potential, but ABCB1 P-gp was found not responsible for the plasma membrane hyperpolarization observed in multidrug resistant cells (35). Here we have cloned and characterized a novel, third member of the human P-gp family encoded on chromosome 7p21-15.3, designated ABCB5 (ATP-binding cassette, subfamily B (MDR/TAP), member ...
P-glycoprotein (P-gp) expressed on human antigen presenting cells (APC) regulates alloantigendependent T-cell activation, but the associated mechanisms are not well understood. Here we demonstrate that P-gp functions in IL-12-dependent monocyte differentiation into dendritic cell (DC) lineages during APC maturation, thereby regulating the capacity of myeloid-derived APCs to elicit alloimmune Th1 responses. Human CD14 + monocytes cultured in vitro in the presence of IL-4/GM-CSF differentiated into CD14 − CD1a + APCs of the immature DC phenotype. In contrast, P-gp blockade during differentiation inhibited CD1a induction, down-regulated CD80 expression, enhanced CD86 expression and induced CD68 expression. APCs differentiated in the presence of P-gp blockade stimulated alloimmune T-cell proliferation significantly less than controls and this effect was associated with 97% inhibition of Th1 IFN-c production, but preserved Th2 IL-5 secretion. MAb-mediated blockade of the P-gp transport substrate IL-12 in the course of APC differentiation also inhibited IFN-c production, while addition of rIL-12 to P-gp-blocked APC differentiation cultures significantly reversed this effect, demonstrating that P-gp functions in APC differentiation in part via IL-12 regulation. Our findings define a novel role for P-gp as a differentiation switch in APC maturation and resultant alloimmune Th1 responses, thereby identifying P-gp as a potential novel therapeutic target in allotransplantation.
TEL is a new member of the ETS family of transcription factors which is rearranged in a number of hematologic malignancies with translocations involving chromosome band 12p13. In some cases, both TEL alleles are affected, resulting in loss of wild-type TEL function in the leukemic cells. In addition, 5% of children with acute lymphoblastic leukemia (ALL) have 12p12-p13 deletions, suggesting that a tumor suppressor gene resides on 12p. These observations led us to consider whether TEL loss of function may contribute to the pathogenesis of ALL. In this report we show that the TEL gene maps between the polymorphic markers D12S89 and D12S98, and we use these flanking markers to screen paired diagnosis and remission samples from 81 children with ALL for loss of heterozygosity (LOH) at the TEL gene locus. Fifteen percent of informative patients showed TEL LOH which was not evident on cytogenetic analysis. Detailed examination of patients with LOH at this locus showed that the critically deleted region included two candidate tumor suppressor genes: TEL and KIP1, the gene encoding the cyclin- dependent kinase inhibitor p27. These studies show that LOH at the TEL locus is a frequent finding in childhood ALL.
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