Type II JAK2 Inhibitor NVP-CHZ868 is Active in Vitro and in Vivo Against JAK2-Dependent B-cell Acute Lymphoblastic Leukemias

Gene expression profiling was performed to define transcriptional programs associated with response to type II JAK2 inhibitor NVP-CHZ868 alone or in combination with dexamethasone in vitro and in vivo. MHH-CALL4 cells harboring a CRLF2 rearrangement and JAK2 I682F mutation were treated with vehicle, CHZ868, dexamethasone, or CHZ868 + dexamethasone combination for 12 hours in triplicate. RNA was then extracted for hybridization on Affymetrix microarrays. CRLF2+ patient-derived xenografts (05-412, 05-440, and 05-537) were treated in vivo for 3 days with vehicle, CHZ868, dexamethasone, or CHZ868 + dexmathasone combination for 3 days and then sacrificed. Transcriptional profiling was performed on unselected splenocytes from these animals.

本研究通过基因表达谱分析，旨在明确II型JAK2抑制剂NVP-CHZ868单药或联合地塞米松在体内外实验中对应的应答相关转录调控程序。将携带CRLF2重排与JAK2 I682F突变的MHH-CALL4细胞分为四组，分别以溶媒、CHZ868、地塞米松及CHZ868+地塞米松联合方案处理，设置三次生物学重复，孵育12小时。随后提取总RNA，用于Affymetrix基因芯片杂交检测。针对CRLF2阳性患者来源异种移植瘤（patient-derived xenografts）（品系编号05-412、05-440及05-537）开展3天的体内给药处理，给药方案分别为溶媒、CHZ868、地塞米松及CHZ868+地塞米松联合方案，随后处死实验动物。采集上述动物未分选的脾脏淋巴细胞，进行转录组谱分析。