Cancer Cell
Volume 27, Issue 3, 9 March 2015, Pages 409-425
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Article
Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

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Highlights

  • ALL can be divided into two distinct subtypes based on pre-BCR function

  • Pre-BCR-induced activation of BCL6 further increased pre-BCR signaling output

  • Pre-BCR inhibitors reduced BCL6 levels and selectively killed pre-BCR+ ALL cells

  • BCL6 represents a biomarker to identify patients with pre-BCR+ ALL

Summary

Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.

Cited by (0)

18

Present address: Institute for Immunology, Ludwig-Maximilians-Universität, 80336 Munich, Germany

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Co-first author

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Co-senior author