Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.
Geng H., Hurtz C., Lenz KB., Chen Z., Baumjohann D., Thompson S., Goloviznina NA., Chen W-Y., Huan J., LaTocha D., Ballabio E., Xiao G., Lee J-W., Deucher A., Qi Z., Park E., Huang C., Nahar R., Kweon S-M., Shojaee S., Chan LN., Yu J., Kornblau SM., Bijl JJ., Ye BH., Ansel KM., Paietta E., Melnick A., Hunger SP., Kurre P., Tyner JW., Loh ML., Roeder RG., Druker BJ., Burger JA., Milne TA., Chang BH., Müschen M.
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.