Select kinases in the pathogenesis of CLL
| . | LYN . | SYK . | PI3Kδ . | BTK . |
|---|---|---|---|---|
| Kinase | TK of the SRC family | TK, of the SYK/ZAP70 family | Lipid kinase | TK of the TEC family |
| Major target substrates | Igα, Igβ, SYK, tyrosine phosphatases | SYK, BLNK, BTK | Phosphatidylinositol PIP2 | PLCγ2, PKCβ |
| Pathways activating the kinase | BCR, CD40, FcR | BCR, FcR, integrin-, chemokine-, C-type lectin signaling | BCR, CD40, BAFF, TLR, IL-4R, IL-7R, RAS | BCR, CD40, BAFF, TLR, FcR, and chemokine signaling |
| Consequences of genetic loss | In mice: reduced BCR signaling, increased IgM levels, lethal autoimmune disease | In mice: partial block at the pro-B-cell stage, complete block at the immature B-cell stage, absence of mature B cells | In mice: absence of B1 and marginal zone B cells, and germinal centers, hypogammaglobulinemia | In patients: block at the pre-B-cell stage, X-linked agammaglobulinemia; in mice: xid with milder phenotype similar to PI3Kδ loss |
| Inhibitors | Dasatinib, | Fostamatinib, | GS-1101 | Ibrutinib,* |
| Bosutinib, | PRT318, P505–15 | AVL-292, | ||
| Bafetinib | Dasatinib, | |||
| Bosutinib |
| . | LYN . | SYK . | PI3Kδ . | BTK . |
|---|---|---|---|---|
| Kinase | TK of the SRC family | TK, of the SYK/ZAP70 family | Lipid kinase | TK of the TEC family |
| Major target substrates | Igα, Igβ, SYK, tyrosine phosphatases | SYK, BLNK, BTK | Phosphatidylinositol PIP2 | PLCγ2, PKCβ |
| Pathways activating the kinase | BCR, CD40, FcR | BCR, FcR, integrin-, chemokine-, C-type lectin signaling | BCR, CD40, BAFF, TLR, IL-4R, IL-7R, RAS | BCR, CD40, BAFF, TLR, FcR, and chemokine signaling |
| Consequences of genetic loss | In mice: reduced BCR signaling, increased IgM levels, lethal autoimmune disease | In mice: partial block at the pro-B-cell stage, complete block at the immature B-cell stage, absence of mature B cells | In mice: absence of B1 and marginal zone B cells, and germinal centers, hypogammaglobulinemia | In patients: block at the pre-B-cell stage, X-linked agammaglobulinemia; in mice: xid with milder phenotype similar to PI3Kδ loss |
| Inhibitors | Dasatinib, | Fostamatinib, | GS-1101 | Ibrutinib,* |
| Bosutinib, | PRT318, P505–15 | AVL-292, | ||
| Bafetinib | Dasatinib, | |||
| Bosutinib |
TK indicates tyrosine kinase.
Ibrutinib and AVL-292 are irreversible inhibitors.