Tonic pre–B-cell receptor (pre-BCR) signaling identifies a unique subset of human ALL.
Major finding: Tonic pre–B-cell receptor (pre-BCR) signaling identifies a unique subset of human ALL.
Concept: Pre-BCR activation by the TCF3–PBX1 fusion induces BCL6, which further increases pre-BCR signaling.
Impact: Pre-BCR+ ALL tumors are selectively sensitive to treatment with pre-BCR inhibitors such as dasatinib.
B-cell receptor (BCR) signaling can be classified as tonic, which acts through SYK and SRC family kinases to activate PI3Kδ, or chronic active, which stimulates multiple downstream pathways, including Bruton tyrosine kinase (BTK). Most mature B-cell malignancies are dependent on BCR signaling and respond to treatment with small-molecule inhibitors of BCR signaling. However, the role of pre-BCR activity in pre-B acute lymphoblastic leukemia (ALL) is unknown. Geng, Hurtz, Lenz, and colleagues found that, although most cases of human pre-B ALL lacked pre-BCR signaling, a subset of tumors was characterized by surface pre-BCR expression and constitutive activation of SRC, SYK, and PI3K–AKT, indicative of tonic pre-BCR signaling. Pre-BCR+ ALL tumors exhibited frequent expression of the transcription factor 3 (TCF3)–pre–B-cell leukemia homeobox 1 (PBX1) oncogenic fusion, which directly induced the expression of genes encoding components of the pre-BCR and downstream signaling. TCF3–PBX1-mediated activation of pre-BCR signaling in these tumors resulted in upregulation of the transcription factor BCL6, which stimulated the expression of pre-BCR–related genes to further increase tonic pre-BCR signaling as part of a positive feedback loop. Depletion or pharmacologic inhibition of BCL6 impaired the growth of pre-BCR+ ALL cells, suggesting that pre-BCR+ ALL tumors are dependent on BCL6 expression. In support of this idea, pre-BCR+ ALL cells, but not pre-BCR− ALL cells, were selectively sensitive to inhibitors of the pre-BCR signaling components SYK, SRC, and BTK, which abolished BCL6 expression and showed antileukemic activity both in vitro and in vivo. In particular, treatment with the dual ABL1/SRC inhibitor dasatinib suppressed leukemic growth and prolonged survival in patient-derived xenograft models of pre-BCR+ ALL. These findings identify pre-BCR signaling as a therapeutic target in pre-B ALL and suggest that BCL6 expression may represent a biomarker of patients who are likely to respond to pre-BCR inhibitors.