In B-ALL cells that express a functional pre-BCR ibrutinib abrogates leukemia cell growth in vitro and in vivo.
Effects of ibrutinib in B-ALL are mediated not only through inhibition of BTK, but also involve BLK inhibition.
Targeting B cell receptor (BCR) signaling is a successful therapeutic strategy in mature B cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR+ B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/AKT signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72 and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cells migration towards CXCL12 and beneath marrow stromal cells, and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both, BTK and B lymphocyte kinase (BLK), are relevant targets of ibrutinib in pre-BCR+ ALL. Consequently, in mouse xenograft models of pre-BCR+ ALL ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ ALL and highlight the importance of ibrutinib effects on alternative kinase targets.
- Submitted June 17, 2016.
- Accepted December 19, 2016.
- Copyright © 2016 American Society of Hematology
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