Pharmacologic hyperactivation of SYK results in negative B-cell selection and cell death in ALL.

  • Major finding: Pharmacologic hyperactivation of SYK results in negative B-cell selection and cell death in ALL.

  • Concept: SYK activation above a maximum threshold engages a checkpoint to delete self-reactive B-cell receptors.

  • Impact: SYK hyperactivation may overcome drug resistance and improve survival in patients with Ph+ ALL.

Negative selection of B cells with attenuated or hyperactivated B-cell receptor (BCR) signaling eliminates cells with nonfunctional or self-reactive BCRs to ensure an intermediate threshold of BCR signaling. Expression of the oncogenic BCR–ABL1 tyrosine kinase in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) results in constitutively active pre-BCR signaling, and most therapeutic strategies for ALL are aimed at inhibiting BCR–ABL1 signaling below a minimum threshold to induce cell death. Chen, Shojaee, and colleagues sought to determine whether pharmacologic hyperactivation of BCR signaling above a maximum threshold would elicit a negative selection checkpoint and result in the killing of ALL cells. Reactivation of immunoreceptor tyrosine-based activation motif–mediated pre-BCR signaling resulted in cell death in patient-derived Ph+ ALL cells. In particular, expression of constitutively active SYK kinase was necessary and sufficient to stimulate cell death in pre-B ALL cells. In an effort to identify pharmacologic means to hyperactivate SYK, the authors found that the immunoreceptor tyrosine-based inhibitory motif (ITIM)–bearing receptors platelet/endothelial cell adhesion molecule 1, CD300A, and leukocyte-associated immunoglobulin-like receptor 1, which negatively regulate SYK, were upregulated in Ph+ ALL and were associated with decreased overall and relapse-free survival. Deletion of ITIM-bearing receptors triggered pre-B ALL cell death in vitro and inhibited leukemia growth in vivo; genetic rescue experiments demonstrated that activation of protein tyrosine phosphatase nonreceptor type 6 (PTPN6) and inositol polyphosphate-5-phosphatase (INPP5D) by ITIM-bearing surface receptors was required for pre-B leukemogenesis in mice. Deletion of Ptpn6 or Inpp5d or treatment with a small-molecule INPP5D inhibitor induced hyperactivation of SYK, resulting in subsequent cell death of patient-derived Ph+ ALL cells, including tyrosine kinase inhibitor–resistant cells, and decreased leukemia burden in mouse models. In sum, these results suggest that hyperactivation of SYK engages negative selection of B cells and may be a viable therapeutic strategy to overcome drug resistance in Ph+ ALL.

Chen Z, Shojaee S, Buchner M, Geng H, Lee JW, Klemm L, et al. Signaling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 2015 Mar 23 [Epub ahead of print].

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