A small molecule Abl kinase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines.
Abelson murine leukemia virus-transformed cell lines have provided a critical model system for studying the regulation of B cell development. However, transformation by v-Abl blocks B cell development, resulting in the arrest of these transformants in an early pre-B cell-like state. We report here that treatment of Abelson virus-transformed pre-B cell lines with the small molecule Abl kinase inhibitor (STI571) results in their differentiation to a late pre-B cell-like state characterized by induction of immunoglobulin (Ig) light chain gene rearrangement. DNA microarray analyses enabled us to identify two genes inhibited by v-Abl that encode the Igk 3' enhancer-binding transcription factors Spi-B and IRF-4. We show that enforced expression of these two factors is sufficient to induce germline Igk transcription in Abelson-transformed pro-B cell lines. This suggests a key role for these factors, and perhaps for c-Abl itself, in the regulated activation of Ig light chain gene rearrangement.
Muljo
Stefan A
SA
University of California, Department of Molecular & Cell Biology, Division of Immunology, 439 Life Sciences Addition, Berkeley, CA 94720-3200, USA.
Schlissel
Mark S
MS
D000011:Abelson murine leukemia virus / Q000235:genetics / Q000472:pathogenicity; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D001483:Base Sequence; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000187:drug effects; D000068877:Imatinib Mesylate; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors*; D010879:Piperazines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics
D001549:Benzamides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016374:Oncogene Proteins v-abl; D010879:Piperazines; D011743:Pyrimidines; D014157:Transcription Factors; C076877:SPIB protein, human; D000068877:Imatinib Mesylate; D004247:DNA; D011505:Protein-Tyrosine Kinases