The BCR-ABL1 Kinase Interferes with Pre-B Cell Receptor Signal Transduction in B Cell Precursor Leukemia Cells.

The BCR-ABL1 kinase expressed in B cell precursor leukemia drives malignant transformation of human pre-B cells. To identify novel target genes of BCR-ABL1-mediated transformation and to elucidate how the oncogenic BCR-ABL1 kinase may interfere with normal pre-B cell receptor signaling, we compared genome-wide gene expression of BCR-ABL1⁺ B cell precursor leukemia cells with their normal counterpart.

While pre-B cell receptor signals are critical for differentiation and survival of normal pre-B cells, nearly all components of pre-B cell receptor-dependent signal transduction were downregulated in the leukemia cells. Surprisingly, BCR-ABL1⁺ leukemia cells mostly even 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 gene rearrangement nonfunctional. However, even BCR-ABL1⁺ leukemia cells harboring a functional V_H gene rearrangement are unresponsive to pre-B cell receptor engagement. Independently from engagement, BCR-ABL1 kinase activity induces activation of PLCg1, resulting in an autonomous oscillatory Ca²⁺ signaling. BCR-ABL1 kinase activity is also linked to the expression of a truncated isoform of the pre-B cell receptor-associated linker molecule SLP65, which acts as a tumor suppressor in mice. Conversely, leukemia subclones surviving inhibition of BCR-ABL1 show responsiveness to antigen receptor engagement and express only full-length SLP65. These cells differentiate into immature B cells expressing Ig light chains.

We conclude that BCR-ABL1 interferes with pre-B cell receptor signal transduction in B cell precursor leukemia cells, while its inhibition reconstitutes the selection for functional (pre-)B cell receptor signaling. Hence, a functional pre-B cell receptor signal-transduction cascade may provide these cells with a potential mechanism to escape apoptotic cell death induced by inhibition of BCR-ABL1.

Figure Legend:BCR-ABL1⁺ leukemia cells were incubated for 48 hours in the presence or absence of 10 μmol/l STI571. Differentiating subclones among the STI571-treated cells replace their pre-B cell receptor by a B cell receptor and were enriched for surface IgM-expression by MACS.

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