UNASSIGNED: We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK).
UNASSIGNED: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs.
UNASSIGNED: Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP.
UNASSIGNED: Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.
未经证实:我们假设第二代和第三代BCR-ABL1TKIs可能通过激活含Rho相关卷曲螺旋激酶(ROCK)引起CVAE。
UNASSIGNED:通过毛细管电泳评估了53名接受TKI的Ph+患者和15名无Ph+白血病的对照患者的外周血单核细胞的ROCK活性(中位随访时间=26个月[Q1-Q3:5-37个月])。
未经证实:接受第二代和第三代TKIs的患者与接受伊马替尼的患者和对照组患者相比,ROCK活性高1.6倍。
未经批准:我们的研究结果表明,在接受BCR-ABL1TKIs的患者中,ROCK活性可能是CVAE的预后指标。