Interference of BCR-ABL1 kinase activity with antigen receptor signaling in B cell precursor leukemia cells.
The chromosomal translocation t,(9;22) resulting in the fusion of the BCR and ABL1 genes, represents a recurrent aberration in B cell precursor leukemia cells. Their normal counterparts, B cell precursor cells, are positively selected for survival signals through the antigen receptor, whose expression requires a functional immunoglobulin heavy chain (IGH) gene rearrangement. Unexpectedly, B cell precursor leukemia cells harboring a BCR-ABL1 gene rearrangement do not depend on antigen receptor mediated survival signals. Genes involved in the signaling cascade of the antigen receptor are silenced and in most cases, the dominant tumor clone does not carry a functional IGH gene rearrangement. However, upon inhibition of the BCR-ABL1 kinase activity by STI571, only leukemia cells expressing an antigen receptor are able to survive. Since resistance to STI571 is frequent in the therapy of BCR-ABL1(+) B cell precursor leukemia, antigen receptor signaling may represent a mechanism through which these cells can temporarily evade STI571-induced apoptosis. This may open a time frame, during which leukemia cells acquire secondary transforming events that confer definitive resistance to STI571.
Klein
Florian
F
Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Feldhahn
Niklas
N
Müschen
Markus
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D042381:Granulocyte Precursor Cells / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015448:Leukemia, B-Cell / Q000201:enzymology* / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl