摘要:Ponatinib是针对BCR-ABL1的酪氨酸激酶抑制剂(TKI),该抑制剂(TKI)成功地用于BCR-ABL1 T315I +慢性髓样白血病(CML)中。但是,在这些患者的治疗过程中可能会出现BCR-ABL1化合物突变,并可能导致耐药性。asciminib是一种新型药物,能够靶向包括BCR-ABL1 T315I在内的大多数BCR-ABL1突变体形式,但仍针对大多数BCR-ABL1 T315I +化合物突变的亚cl孔无效。我们证明,Asciminib与Ponatinib协同诱导患者衍生的CML细胞系的生长避孕和凋亡,以及具有BCR-ABL1 T315I或T315I(T315I-a)的鼠BA/F3细胞。asciminib和Ponatinib还对BCR-ABL1转化细胞中的CRKL磷酸化产生了合作作用。羟基酸(HU)进一步增强了药物组合“ asciminib + ponatinib”的生长抑制作用,该药物最近被描述为抑制BCR-ABL1 T315I + CML细胞的增殖。合作药物作用。最重要的是,我们能够证明“ Asciminib+Ponatinib”和“ Asciminib+Ponatinib+Hu”的组合产生了CD34+ /CD38-CML干细胞中的Syner Gister凋亡诱导效果,该干细胞从患有慢性相CML或BCR-ABL1 T315I+CML的患者中获得。一起,assiminib,Ponatinib和Hu协同在多耐CML细胞中产生抗白血病作用,包括携带T315I+ BCR-ABL1化合物突变和CML干细胞的细胞。需要在即将进行的临床试验的框架内评估该TKI组合的临床功效。
11-12 故障事件数据寄存器................................................................................ 11-38 11-13 故障事件地址寄存器................................................................................ 11-39 11-14 故障事件高位地址寄存器........................................................................ 11-40 11-15 故障记录寄存器...................................................................................... 11-41 11-16 受保护的存储器启用寄存器...................................................................... 11-44 11-17 受保护的低位存储器基址寄存器...................................................................... 11-45 11-18 受保护的低位存储器限制寄存器...................................................................... 11-46 11-19 受保护的高位存储器基址寄存器...................................................................... 11-47 11-20 受保护的高位存储器限制寄存器...................................................................... 11-48 11-21 无效队列头寄存器................................................................................ 11-50 11-22 无效队列尾部寄存器.................................................................. 11-51 11-23 无效队列地址寄存器............................................................... 11-52 11-24 无效完成状态寄存器............................................................... 11-53 11-25 无效事件控制寄存器............................................................... 11-54 11-26 无效事件数据寄存器............................................................... 11-55 11-27 无效事件地址寄存器................................................................. 11-56 11-28 无效事件高位地址寄存器.................................................................... 11-57 11-29 无效队列错误记录寄存器.................................................................... 11-58 11-30 中断重映射表地址寄存器............................................................. 11-60 11-31 页面请求队列头寄存器......................................................................... 11-61 11-32 页面请求队列尾部寄存器......................................................................... 11-62 11-33 页面请求队列地址寄存器...................................................................... 11-63 11-34 页面请求状态寄存器.................................................................... 11-64 11-35 页面请求事件控制寄存器............................................................... 11-65 11-36 页面请求事件数据寄存器............................................................... 11-66 11-37 页面请求事件地址寄存器....................................................................... 11-67 11-38 页面请求事件高位地址寄存器.................................................................... 11-68 11-39 MTRR 能力寄存器.................................................................................... 11-69 11-40 MTRR 默认类型寄存器........................................................................................................ 11-70 11-41 固定范围 MTRR 格式.............................................................................. 11-71 11-42 可变范围 MTRR 格式.............................................................................. 11-73 11-43 性能监控寄存器的示例寄存器布局.................................................... 11-76 11-44 性能监控能力寄存器...................................................................... 11-77 11-45 性能监控配置偏移寄存器......................................................................... 11-79 11-46 性能监控冻结偏移寄存器......................................................................... 11-80 11-47 性能监控溢出偏移寄存器......................................................................... 11-81 11-48 性能监控计数器偏移寄存器......................................................................... 11-82 11-49 性能监控中断状态寄存器......................................................................... 11-83 11-50 性能监控中断控制寄存器......................................................................... 11-84 11-51 性能监控中断数据寄存器............................................................. 11-85 11-52 性能监控中断地址寄存器 .............................................................. 11-86 11-53 性能监控中断高位地址寄存器 .............................................................. 11-87 11-54 性能监控冻结状态寄存器 .............................................................. 11-88 11-55 性能监控溢出状态寄存器 .............................................................. 11-89 11-56 性能监控事件能力寄存器 ............................................................. 11-90 11-57 性能监控计数器配置寄存器 ............................................................. 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器 ............................................. 11-93 11-59 性能监控域 ID 过滤器配置寄存器 ............................................. 11-94 11-60 性能监控 PASID 过滤器配置寄存器 ............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器 ............................................. 11-96 11-62 性能监控页表级过滤器配置寄存器 ............................................. 11-97 11-63 性能监控计数器能力寄存器....................................................... 11-98 11-64 性能监控计数器事件能力寄存器................................................... 11-99 11-65 性能监控计数器寄存器................................................................... 11-100 11-66 增强命令寄存器............................................................................... 11-101........................................................... 11-77 11-45 性能监控配置偏移寄存器 .............................................................. 11-79 11-46 性能监控冻结偏移寄存器 .............................................................. 11-80 11-47 性能监控溢出偏移寄存器 .............................................................. 11-81 11-48 性能监控计数器偏移寄存器 .............................................................. 11-82 11-49 性能监控中断状态寄存器 ............................................................. 11-83 11-50 性能监控中断控制寄存器 ............................................................. 11-84 11-51 性能监控中断数据寄存器 ............................................................. 11-85 11-52 性能监控中断地址寄存器 ............................................................. 11-86 11-53 性能监控中断高位地址寄存器 ............................................................. 11-87 11-54 性能监控冻结状态寄存器 ............................................................. 11-88 11-55 性能监控溢出状态寄存器 ............................................................. 11-89 11-56 性能监控事件能力寄存器..................................................... 11-90 11-57 性能监控计数器配置寄存器..................................................... 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器..................................... 11-93 11-59 性能监控域 ID 过滤器配置寄存器..................................... 11-94 11-60 性能监控 PASID 过滤器配置寄存器............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器..................................... 11-96 11-62 性能监控页表级过滤器配置寄存器..................................... 11-97 11-63 性能监控计数器能力寄存器..................................................... 11-98 11-64 性能监控计数器事件能力寄存器..................................................... 11-99 11-65 性能监控计数器寄存器..................................................... 11-100 11-66 增强命令寄存器..................................................................... 11-101........................................................... 11-77 11-45 性能监控配置偏移寄存器 .............................................................. 11-79 11-46 性能监控冻结偏移寄存器 .............................................................. 11-80 11-47 性能监控溢出偏移寄存器 .............................................................. 11-81 11-48 性能监控计数器偏移寄存器 .............................................................. 11-82 11-49 性能监控中断状态寄存器 ............................................................. 11-83 11-50 性能监控中断控制寄存器 ............................................................. 11-84 11-51 性能监控中断数据寄存器 ............................................................. 11-85 11-52 性能监控中断地址寄存器 ............................................................. 11-86 11-53 性能监控中断高位地址寄存器 ............................................................. 11-87 11-54 性能监控冻结状态寄存器 ............................................................. 11-88 11-55 性能监控溢出状态寄存器 ............................................................. 11-89 11-56 性能监控事件能力寄存器..................................................... 11-90 11-57 性能监控计数器配置寄存器..................................................... 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器..................................... 11-93 11-59 性能监控域 ID 过滤器配置寄存器..................................... 11-94 11-60 性能监控 PASID 过滤器配置寄存器............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器..................................... 11-96 11-62 性能监控页表级过滤器配置寄存器..................................... 11-97 11-63 性能监控计数器能力寄存器..................................................... 11-98 11-64 性能监控计数器事件能力寄存器..................................................... 11-99 11-65 性能监控计数器寄存器..................................................... 11-100 11-66 增强命令寄存器..................................................................... 11-10111-85 11-52 性能监控中断地址寄存器 .............................................................. 11-86 11-53 性能监控中断高位地址寄存器 .............................................................. 11-87 11-54 性能监控冻结状态寄存器 .............................................................. 11-88 11-55 性能监控溢出状态寄存器 .............................................................. 11-89 11-56 性能监控事件能力寄存器 ............................................................. 11-90 11-57 性能监控计数器配置寄存器 ............................................................. 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器 ............................................. 11-93 11-59 性能监控域 ID 过滤器配置寄存器 ............................................. 11-94 11-60 性能监控 PASID 过滤器配置寄存器 ............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器 ............................................. 11-96 11-62 性能监控页表级过滤器配置寄存器 ............................................. 11-97 11-63 性能监控计数器能力寄存器....................................................... 11-98 11-64 性能监控计数器事件能力寄存器................................................... 11-99 11-65 性能监控计数器寄存器................................................................... 11-100 11-66 增强命令寄存器............................................................................... 11-10111-85 11-52 性能监控中断地址寄存器 .............................................................. 11-86 11-53 性能监控中断高位地址寄存器 .............................................................. 11-87 11-54 性能监控冻结状态寄存器 .............................................................. 11-88 11-55 性能监控溢出状态寄存器 .............................................................. 11-89 11-56 性能监控事件能力寄存器 ............................................................. 11-90 11-57 性能监控计数器配置寄存器 ............................................................. 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器 ............................................. 11-93 11-59 性能监控域 ID 过滤器配置寄存器 ............................................. 11-94 11-60 性能监控 PASID 过滤器配置寄存器 ............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器 ............................................. 11-96 11-62 性能监控页表级过滤器配置寄存器 ............................................. 11-97 11-63 性能监控计数器能力寄存器....................................................... 11-98 11-64 性能监控计数器事件能力寄存器................................................... 11-99 11-65 性能监控计数器寄存器................................................................... 11-100 11-66 增强命令寄存器............................................................................... 11-101
11-12 故障事件数据寄存器................................................................................ 11-38 11-13 故障事件地址寄存器................................................................................ 11-39 11-14 故障事件高位地址寄存器........................................................................ 11-40 11-15 故障记录寄存器...................................................................................... 11-41 11-16 受保护的存储器启用寄存器...................................................................... 11-44 11-17 受保护的低位存储器基址寄存器...................................................................... 11-46 11-18 受保护的低位存储器限制寄存器...................................................................... 11-47 11-19 受保护的高位存储器基址寄存器...................................................................... 11-48 11-20 受保护的高位存储器限制寄存器...................................................................... 11-49 11-21 无效队列头寄存器................................................................................ 11-50 11-22 无效队列尾部寄存器.................................................................. 11-51 11-23 无效队列地址寄存器............................................................... 11-52 11-24 无效完成状态寄存器............................................................... 11-53 11-25 无效事件控制寄存器............................................................... 11-54 11-26 无效事件数据寄存器............................................................... 11-55 11-27 无效事件地址寄存器................................................................. 11-56 11-28 无效事件高位地址寄存器.................................................................... 11-57 11-29 无效队列错误记录寄存器.................................................................... 11-58 11-30 中断重映射表地址寄存器............................................................. 11-60 11-31 页面请求队列头寄存器......................................................................... 11-61 11-32 页面请求队列尾部寄存器......................................................................... 11-62 11-33 页面请求队列地址寄存器...................................................................... 11-63 11-34 页面请求状态寄存器.................................................................... 11-64 11-35 页面请求事件控制寄存器............................................................... 11-65 11-36 页面请求事件数据寄存器............................................................... 11-66 11-37 页面请求事件地址寄存器....................................................................... 11-67 11-38 页面请求事件高位地址寄存器.................................................................... 11-68 11-39 MTRR 能力寄存器.................................................................................... 11-69 11-40 MTRR 默认类型寄存器........................................................................................................ 11-70 11-41 固定范围 MTRR 格式.............................................................................. 11-71 11-42 可变范围 MTRR 格式.............................................................................. 11-73 11-43 性能监控寄存器的示例寄存器布局.................................................... 11-76 11-44 性能监控能力寄存器...................................................................... 11-77 11-45 性能监控配置偏移寄存器......................................................................... 11-79 11-46 性能监控冻结偏移寄存器......................................................................... 11-80 11-47 性能监控溢出偏移寄存器......................................................................... 11-81 11-48 性能监控计数器偏移寄存器......................................................................... 11-82 11-49 性能监控中断状态寄存器......................................................................... 11-83 11-50 性能监控中断控制寄存器......................................................................... 11-84 11-51 性能监控中断数据寄存器............................................................. 11-85 11-52 性能监控中断地址寄存器 .............................................................. 11-86 11-53 性能监控中断高位地址寄存器 .............................................................. 11-87 11-54 性能监控冻结状态寄存器 .............................................................. 11-88 11-55 性能监控溢出状态寄存器 .............................................................. 11-89 11-56 性能监控事件能力寄存器 ............................................................. 11-90 11-57 性能监控计数器配置寄存器 ............................................................. 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器 ............................................. 11-93 11-59 性能监控域 ID 过滤器配置寄存器 ............................................. 11-94 11-60 性能监控 PASID 过滤器配置寄存器 ............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器 ............................................. 11-96 11-62 性能监控页表级过滤器配置寄存器 ............................................. 11-97 11-63 性能监控计数器能力寄存器....................................................... 11-98 11-64 性能监控计数器事件能力寄存器................................................... 11-99 11-65 性能监控计数器寄存器................................................................... 11-100 11-66 增强命令寄存器............................................................................... 11-101........................................................... 11-77 11-45 性能监控配置偏移寄存器 .............................................................. 11-79 11-46 性能监控冻结偏移寄存器 .............................................................. 11-80 11-47 性能监控溢出偏移寄存器 .............................................................. 11-81 11-48 性能监控计数器偏移寄存器 .............................................................. 11-82 11-49 性能监控中断状态寄存器 ............................................................. 11-83 11-50 性能监控中断控制寄存器 ............................................................. 11-84 11-51 性能监控中断数据寄存器 ............................................................. 11-85 11-52 性能监控中断地址寄存器 ............................................................. 11-86 11-53 性能监控中断高位地址寄存器 ............................................................. 11-87 11-54 性能监控冻结状态寄存器 ............................................................. 11-88 11-55 性能监控溢出状态寄存器 ............................................................. 11-89 11-56 性能监控事件能力寄存器..................................................... 11-90 11-57 性能监控计数器配置寄存器..................................................... 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器..................................... 11-93 11-59 性能监控域 ID 过滤器配置寄存器..................................... 11-94 11-60 性能监控 PASID 过滤器配置寄存器............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器..................................... 11-96 11-62 性能监控页表级过滤器配置寄存器..................................... 11-97 11-63 性能监控计数器能力寄存器..................................................... 11-98 11-64 性能监控计数器事件能力寄存器..................................................... 11-99 11-65 性能监控计数器寄存器..................................................... 11-100 11-66 增强命令寄存器..................................................................... 11-101........................................................... 11-77 11-45 性能监控配置偏移寄存器 .............................................................. 11-79 11-46 性能监控冻结偏移寄存器 .............................................................. 11-80 11-47 性能监控溢出偏移寄存器 .............................................................. 11-81 11-48 性能监控计数器偏移寄存器 .............................................................. 11-82 11-49 性能监控中断状态寄存器 ............................................................. 11-83 11-50 性能监控中断控制寄存器 ............................................................. 11-84 11-51 性能监控中断数据寄存器 ............................................................. 11-85 11-52 性能监控中断地址寄存器 ............................................................. 11-86 11-53 性能监控中断高位地址寄存器 ............................................................. 11-87 11-54 性能监控冻结状态寄存器 ............................................................. 11-88 11-55 性能监控溢出状态寄存器 ............................................................. 11-89 11-56 性能监控事件能力寄存器..................................................... 11-90 11-57 性能监控计数器配置寄存器..................................................... 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器..................................... 11-93 11-59 性能监控域 ID 过滤器配置寄存器..................................... 11-94 11-60 性能监控 PASID 过滤器配置寄存器............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器..................................... 11-96 11-62 性能监控页表级过滤器配置寄存器..................................... 11-97 11-63 性能监控计数器能力寄存器..................................................... 11-98 11-64 性能监控计数器事件能力寄存器..................................................... 11-99 11-65 性能监控计数器寄存器..................................................... 11-100 11-66 增强命令寄存器..................................................................... 11-10111-85 11-52 性能监控中断地址寄存器 .............................................................. 11-86 11-53 性能监控中断高位地址寄存器 .............................................................. 11-87 11-54 性能监控冻结状态寄存器 .............................................................. 11-88 11-55 性能监控溢出状态寄存器 .............................................................. 11-89 11-56 性能监控事件能力寄存器 ............................................................. 11-90 11-57 性能监控计数器配置寄存器 ............................................................. 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器 ............................................. 11-93 11-59 性能监控域 ID 过滤器配置寄存器 ............................................. 11-94 11-60 性能监控 PASID 过滤器配置寄存器 ............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器 ............................................. 11-96 11-62 性能监控页表级过滤器配置寄存器 ............................................. 11-97 11-63 性能监控计数器能力寄存器....................................................... 11-98 11-64 性能监控计数器事件能力寄存器................................................... 11-99 11-65 性能监控计数器寄存器................................................................... 11-100 11-66 增强命令寄存器............................................................................... 11-10111-85 11-52 性能监控中断地址寄存器 .............................................................. 11-86 11-53 性能监控中断高位地址寄存器 .............................................................. 11-87 11-54 性能监控冻结状态寄存器 .............................................................. 11-88 11-55 性能监控溢出状态寄存器 .............................................................. 11-89 11-56 性能监控事件能力寄存器 ............................................................. 11-90 11-57 性能监控计数器配置寄存器 ............................................................. 11-91 11-58 性能监控请求者 ID 过滤器配置寄存器 ............................................. 11-93 11-59 性能监控域 ID 过滤器配置寄存器 ............................................. 11-94 11-60 性能监控 PASID 过滤器配置寄存器 ............................................. 11-95 11-61 性能监控地址类型过滤器配置寄存器 ............................................. 11-96 11-62 性能监控页表级过滤器配置寄存器 ............................................. 11-97 11-63 性能监控计数器能力寄存器....................................................... 11-98 11-64 性能监控计数器事件能力寄存器................................................... 11-99 11-65 性能监控计数器寄存器................................................................... 11-100 11-66 增强命令寄存器............................................................................... 11-101