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¹ Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
² Institute for Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
³ Institute for Neurophysiology Universität zu Köln, 50931 Cologne, Germany
⁴ Department of Hematology, University Hospital, 60590 Frankfurt/Main, Germany

Address correspondence to Markus Müschen, Laboratory for Molecular Stem Cell Biology, Institute for Transplantation Diagnostics and Cell Therapeutics, Building 14.80, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany. Phone: 49-211-811-9964; Fax: 49-221-811-9961; email: markus.mueschen{at}itz.uni-duesseldorf.de

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 V_H gene rearrangements, which may have rendered an initially productive V_H region gene nonfunctional. Even BCR-ABL1⁺ ALL cells harboring a functional V_H 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.

Key Words: immunoglobulin • SLP65 • differentiation • STI571 • V(D)J recombination

Abbreviations used in this paper: ALL, acute lymphoblastic leukemia; CMP, common myeloid progenitor cell; cRSS, cryptic recombination signal sequence; GCB, germinal center B cell; HSC, hematopoietic progenitor cell; KDE, deleting element; MBC, memory B cell; NBC, naive B cell; SAGE, serial analysis of gene expression; TLP, T lymphoid precursor.

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