Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia
23.03.2015
Chen Z, Shojaee S, Buchner M, Geng H, Lee JW, Klemm L, Titz B, Graeber TG, Park E, Tan YX, Satterthwaite A, Paietta E, Hunger SP, Willman CL, Melnick A, Loh ML, Jung JU, Coligan JE, Bolland S, Mak TW, Limnander A, Jumaa H, Reth M, Weiss A, Lowell CA, Müschen M.
Nature. 2015;521(7552):357-61
B cell acute lymphoblastic leukaemia, or B?ALL, is the most common tumour disease in children and also occurs in adults. It develops when signalling pathways in immature B cells, or pre?B cells, are dysregulated. B cells are selected for an intermediate level of B?cell antigen receptor (BCR) signalling strength and we previously have found that a kinase?phosphatase equilibrium is controlling the BCR activation threshold. In 25 percent of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR?ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre?BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation— above a maximum threshold—will engage a deletional checkpoint for removal of self?reactive B cells and selectively kill ALL cells. Unlike normal pre?B cells, patient?derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. When these inhibiting receptors or the associated phosphatases were shut off, the B?ALL tumour cells died instantly. Thus, despite oncogenic transformation, the basic mechanism of negative selection are still functional in ALL cells. We demonstrated that pharmacological hyperactivation of SYK and engagement of negative B?cell selection represents a promising new strategy to overcome drug resistance in human ALL.
