Clonal variation in the B-lineage acute lymphoblastic leukemia response to multiple cytokines and bone marrow stromal cells.
The acquisition of genetic abnormalities in human B-lineage acute lymphoblastic leukemia (ALL) culminates in the clonal expansion of bone marrow (BM)-derived leukemic blasts. However, the response of leukemic cells to signals transduced by the BM microenvironment is not completely understood. The present study describes a new human B-lineage ALL cell line designated BLIN-4 (B LINeage-4). BLIN-4 cells respond to multiple cytokines/human BM stromal cell-derived molecules. One subline (BLIN-4E) undergoes cell death in the absence of BM stromal cells or cytokines and slowly proliferates on human BM stromal cells supplemented with interleukin (IL)-7 + FLT3-ligand. Another subline (BLIN-4L) slowly proliferates in the absence of cytokines and BM stromal cells and shows robust proliferation on BM stromal cells supplemented with IL-7 + FLT3-ligand. Although human BM stromal cells are comparable with IL-7 + FLT3-ligand in supporting proliferation of BLIN-4L cells, neutralizing antibody experiments demonstrate that BLIN-4L expansion on BM stromal cells is IL-7/FLT3-ligand independent. BLIN-4L could also respond to human thymic stromal lymphopoietin. BLIN-4E and BLIN-4L have the identical immunoglobulin heavy chain rearrangement and a CD10(+)/CD19(+)/CD20(-)/CD22(+)/CD40(+)/mu heavy chain(-) phenotype. The original BM leukemic blasts harbored a ring chromosome 4 with a low percentage of cells also having either trisomy 8 or trisomy 18. The BLIN-4 sublines maintained the ring chromosome 4, but the trisomy 8 and trisomy 18 segregated into BLIN-4E and BLIN-4L, respectively. Thus, the BLIN-4 sublines exhibit biological characteristics consistent with a potential evolution in B-lineage ALL involving subclones with decreasing requirements on the BM microenvironment.
Shah
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N
Department of Laboratory Medicine/Pathology, University of Minnesota Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Oseth
L
L
Tran
H
H
Hirsch
B
B
LeBien
T W
TW
D000293:Adolescent; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology; D008565:Membrane Proteins / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3; D000094632:Thymic Stromal Lymphopoietin
D017077:Culture Media, Conditioned; D016207:Cytokines; D015851:Interleukin-7; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020395:Receptors, Interleukin-7; C084881:flt3 ligand protein; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D000094632:Thymic Stromal Lymphopoietin