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Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK

Ekaterina Kim, Christian Hurtz, Stefan Koehrer, Zhiqiang Wang, Sriram Balasubramanian, Betty Y. Chang, Markus Müschen, R. Eric Davis and Jan A. Burger

Key points

  • 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.

Abstract

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.