The BCR-ABL1 Kinase Bypasses Selection for the Expression of a Pre–B Cell Receptor in Pre–B Acute Lymphoblastic Leukemia Cells
Open Access
- 1 March 2004
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 199 (5), 673-685
- https://doi.org/10.1084/jem.20031637
Abstract
The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of human pre–B cells. Comparing genome-wide gene expression profiles of BCR-ABL1+ pre–B ALL and normal bone marrow pre–B cells by serial analysis of gene expression, many genes involved in pre–B cell receptor signaling are silenced in the leukemia cells. Although normal pre–B cells are selected for the expression of a functional pre–B cell receptor, BCR-ABL1+ ALL cells mostly do not harbor a productively rearranged IGH allele. In these cases, we identified traces of secondary VH gene rearrangements, which may have rendered an initially productive VH region gene nonfunctional. Even BCR-ABL1+ ALL cells harboring a functional VH region gene are unresponsive to pre–B cell receptor engagement and exhibit autonomous oscillatory Ca2+ signaling activity. Conversely, leukemia subclones surviving inhibition of BCR-ABL1 by STI571 restore responsiveness to antigen receptor engagement and differentiate into immature B cells expressing immunoglobulin light chains. BCR-ABL1 kinase activity is linked to defective pre–B cell receptor signaling and the expression of a truncated isoform of the pre–B cell receptor–associated linker molecule SLP65. Also in primary leukemia cells, truncated SLP65 is expressed before but not after treatment of the patients with STI571. We conclude that inhibition of BCR-ABL1 reconstitutes selection for leukemia cells expressing a functional (pre–) B cell receptor.Keywords
This publication has 32 references indexed in Scilit:
- Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemiaNature, 2003
- Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell developmentNature Immunology, 2003
- A small molecule Abl kinase inhibitor induces differentiation of Abelson virus–transformed pre-B cell linesNature Immunology, 2002
- The adaptor protein SLP-65 acts as a tumor suppressor that limits pre-B cell expansionNature Immunology, 2002
- Silencing of B Cell Receptor Signals in Human Naive B CellsThe Journal of Experimental Medicine, 2002
- Control of Pre-BCR Signaling by Pax5-Dependent Activation of the BLNK GeneImmunity, 2002
- MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemiaNature Genetics, 2001
- Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia ChromosomeNew England Journal of Medicine, 2001
- JAK-STAT signaling activated by Abl oncogenesOncogene, 2000
- Clonal selection and learning in the antibody systemNature, 1996