Table 1:
Used JAK2 mutations and their presumed mode of action or experimental 530 rationale. See also Figure 1.
| Mutation | Substructure | Rationale / mode of action | Reference |
|---|---|---|---|
| Y119E | FERM F1 | Mimics Y119 phosphorylation. Previously reported to induce dissociation of JAK2 from receptor. | 29,32 |
| V511R | SH2 | Designed to disrupt SH2-JH2 linker from FERMSH2. | - |
| F537A | SH2-JH2 link | F537 proposed to stack with F595 in JAK2 JH2 WT. Known to inhibit V617F. | 26 |
| K539L | SH2-JH2 link | Activating by unknown mechanism. Causes PV. | 38 |
| G552A + G554A | JH2 β1: Glyrich loop | Designed to remove flexible glycines usually needed for ATP binding. | 16 |
| I559F | JH2 β2 | Designed to sterically inhibit ATP binding. Verified to inhibit ATP binding 16. | 16 |
| K581A | JH2 β3 | Removes conserved β3 lysine. | 16,39 |
| E592R | JH2 αC | Outer face of JH2 αC | 12 |
| F595A | JH2 αC | Inner face of JH2 αC. Known to inhibit V617F and others by potentially destabilizing JH2 and making space for F617 (ref 12). | 12,23–25 |
| E596R | JH2 αC | Outer face of JH2 αC. Known to inhibit V617F and others. Mechanism unknown. | 22 |
| V617F | JH2 β4-β5 loop | Activating, potentially by disturbing SH2-JH2 linker. Causes MPNs. | 40–43 |
| K677E | JH2 β6-β7 loop | Designed to inhibit ATP binding electrostatically. Verified to inhibit ATP binding. | 16 |
| R683S | JH2 β7-β8 loop | Activating, probably by breaking R683-D873 interaction over inhibitory JH2-JH1 interface. Causes ALL. | 44,45 |
| T875N | JH1 β2-β3 loop | Activating, mechanism probably similar to R683S. Causes AMKL. | 46 |
| L884P | JH1 β3-αC loop | Activating by unknown mechanism. Homologous to JAK3 L857P found in ALL. | 47 |
| E896A + E900A | JH1 αC | Outer face of JH1 αC. | - |
| D976N | JH1 β6-β7 loop | D in HRD. Mutation is catalytically inactive (i.e., kinase dead). | - |