Agarwal Puneet, Zhang Bin, Ho Yinwei, Cook Amy, Li Ling, Mikhail Fady M, Wang Youzhen, McLaughlin Margaret E, Bhatia Ravi
Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA.
Blood. 2017 Feb 23;129(8):1008-1020. doi: 10.1182/blood-2016-05-714089. Epub 2016 Dec 23.
Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) has limited efficacy against leukemia stem cells (LSC) responsible for disease propagation, and most CML patients require continued TKI treatment to maintain remission. LSC maintenance is related, at least in part, to signals from the bone marrow microenvironment (BMM). Our previous studies have shown that Wnt signaling from the BMM contributes to preservation of CML LSC following TKI treatment. Secretion of Wnt ligands requires their modification by the -acyl transferase Porcupine (PORCN). Here we investigated the activity of a potent and selective PORCN inhibitor, WNT974, against CML stem and progenitor cells. WNT974 efficiently antagonized Wnt signaling in human CML CD34 cells, and in combination with the TKI nilotinib (NIL) significantly enhanced inhibition of proliferation and colony-forming potential of CML stem and progenitor cells and reduced their growth in immunodeficient mice in vivo, in comparison with NIL alone. Treatment of transgenic CML mice in vivo with NIL in combination with WNT974 significantly reduced leukemic stem and progenitor cell numbers, reduced regeneration of leukemic long-term hematopoietic stem cells in secondary transplant recipients, and enhanced survival of mice after discontinuation of treatment, in comparison with NIL alone. CML progenitors demonstrated enhanced sensitivity to Wnt stimulation, associated with increased expression of the FZD4 receptor. FZD4 knockdown inhibited CML progenitor growth. These results support further investigation of PORCN targeting to inhibit Wnt secretion and signaling and enhance targeting of CML stem cells while sparing their normal counterparts.
酪氨酸激酶抑制剂（TKI）治疗慢性粒细胞白血病（CML）对负责疾病传播的白血病干细胞（LSC）疗效有限，大多数CML患者需要持续进行TKI治疗以维持缓解状态。LSC的维持至少部分与骨髓微环境（BMM）发出的信号有关。我们之前的研究表明，BMM发出的Wnt信号有助于TKI治疗后CML-LSC的保存。Wnt配体的分泌需要经酰基转移酶Porcupine（PORCN）修饰。在此，我们研究了一种强效且选择性的PORCN抑制剂WNT974对CML干细胞和祖细胞的活性。与单独使用尼洛替尼（NIL）相比，WNT974能有效拮抗人CML CD34细胞中的Wnt信号，并与TKI尼洛替尼（NIL）联合使用，显著增强了对CML干细胞和祖细胞增殖及集落形成潜力的抑制作用，并降低了它们在免疫缺陷小鼠体内的生长。与单独使用NIL相比，在体内用NIL联合WNT974治疗转基因CML小鼠，可显著减少白血病干细胞和祖细胞数量，降低二次移植受体中白血病长期造血干细胞的再生能力，并提高停药后小鼠的存活率。CML祖细胞对Wnt刺激表现出更高的敏感性，这与FZD4受体表达增加有关。敲低FZD4可抑制CML祖细胞的生长。这些结果支持进一步研究靶向PORCN以抑制Wnt分泌和信号传导，并增强对CML干细胞的靶向作用，同时保留其正常对应细胞。
