CS-1, a novel c-kithi+ acute myeloid leukemia cell line with dendritic cell differentiation capacity and absent immunogenicity.
Complex cytogenetic abnormalities confer dismal prognoses in myeloid malignancies. Even bone marrow transplantation from siblings or matched unrelated donors offer minimal chances for cure, suggesting that these cases are not only refractory to chemotherapy but also resist the graft-vs.-leukemia effect. We herein describe the first permanent, factor-independent c-kit(hi+) cell line CS-1 derived from an unrelated donor stem cell transplanted patient with relapsed acute myeloid leukemia (AML)-M5a of high-risk karyotype [monosomy 7, t(2;11)(q31;p13), t(10;12)(q24;q24)]. Having the same karyotype, CS-1 exhibits an autonomous growth pattern and responds to stem cell factor (SCF). CS-1 did not induce T cell activation in mixed-lymphocyte-tumor-cultures (MLTCs) and, when used as third party stimulators, decreased T cell proliferation in mixed-lymphocyte reactions (MLRs). Cytokines added exogenously or secreted from bystander T cells caused CS-1 to differentiate into dendritic cells (DCs). CS-1-derived DCs, in contrast to DCs originating from non-malignant CD34(+) progenitor cells, had virtually no T cell stimulatory effect, indicating that CS-1 is both immunosuppressive and poorly immunogenic. These properties may partially be due to the detected downregulation of costimulatory molecules and appear to involve a soluble factor. CS-1 cells injected subcutaneously (s.c.) to non-obese diabetes/severe combined immunodeficient (NOD/SCID) mice produced solid tumors, disseminating into bone marrow and spleen. The data show that transforming AML blasts with high-risk karyotype into DCs is insufficient to restore their immunogenicity and that the CS-1 cell line is useful to identify tumor-related immunosuppressive mechanisms in vitro and in vivo.
Erben
Ulrike
U
Department of Hematology, Oncology and Transfusion Medicine, University Hospital Benjamin Franklin, Free University, Berlin, Germany.
Thiel
Eckhard
E
Bittroff-Leben
Alexandra
A
Schoch
Claudia
C
Fichtner
Iduna
I
Dürkop
Horst
H
Notter
Michael
M
D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation; D002455:Cell Division; D002648:Child; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D007621:Karyotyping; D007948:Leukemia, Monocytic, Acute / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000276:immunology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D013154:Spleen / Q000473:pathology; D019089:Stem Cell Factor / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D016207:Cytokines; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit