Exploring Pre-B Cell Receptor Signalling as a Therapeutic Target in Acute Lymphoblastic Leukaemia

Introduction:

Acute lymphoblastic leukaemia (ALL) cells hijack components of precursor-B cell receptor (Pre-BCR) signalling and this dependency may be amenable to therapeutic exploitation. A number of TKIs are showing great promise in the clinic for other leukemia subtypes which warrant preclinical evaluation in childhood ALL. These include CAL-101 (PI3K-δ inhibitor), Ibrutinib (BTK inhibitor), Fostamatinib R406 (SYK inhibitor) and Dasatinib (BCR-ABL/SRC inhibitor).

Methods:

Thus, in this study, we used ALL cell lines and patient-derived xenograft cells and characterised Pre-BCR expression and activity, investigated the sensitivity of cells to single TKIs and combination with Dexamethasone in vitro.

Results:

ALL cell lines were resistant to CAL-101 and Ibrutinib, but modest sensitivity was seen to R406 and Dasatinib. CAL-101 and Dasatinib were cytostatic, while Ibrutinib and R406 were associated with cell cycle arrest and significant apoptosis. Pre-BCR positive cells were more sensitive to Dasatinib and R406. Synergism was seen after co-treatment of TKIs with Dexamethasone and for R406 and Dasatinib was strongly synergistic with increased apoptosis seen in PreB 697 and the GC resistant lines, Nalm-6 and R3F9. Synergism was associated with a significant increase in expression of the GR target, GILZ.

Conclusion:

Pre-BCR positive ALLs were associated with Dasatinib and R406 sensitivity, with marked synergism seen in combination with Dexamethasone and warrants further evaluation as a potential novel therapeutic approach for high risk, relapsed ALL.

No conflict of interest has been declared by the author(s).