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

摘要: Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature malignancies. Precursor BCR (pre-BCR) signaling, which critical during normal B lymphopoiesis, also plays an important role pre-BCR+ cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action BTK inhibitor ibrutinib preclinical models B-ALL. Pre-BCR+ ALL cells were exquisitely sensitive to at therapeutically relevant drug concentrations. In ALL, thwarted autonomous induced pre-BCR resulting deactivation PI3K/Akt signaling. Ibrutinib modulated expression regulators (PTPN6, CD22, CD72, PKCβ) substantially reduced BCL6 levels. inhibited migration toward CXCL12 beneath marrow stromal CD44 expression. CRISPR-Cas9 gene editing revealed that both lymphocyte kinase (BLK) are targets ALL. Consequently, mouse xenograft treatment significantly prolonged survival. Combination with dexamethasone or vincristine demonstrated synergistic against These data corroborate as promising targeted agent for highlight importance effects on alternative targets.