Ruxolitinib/nilotinib cotreatment inhibits leukemia-propagating cells in Philadelphia chromosome-positive ALL.
Ruxolitinib/nilotinib cotreatment inhibits leukemia-propagating cells in Philadelphia chromosome-positive ALL.
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鲁索替尼/尼洛替尼联合治疗可抑制费城染色体阳性 ALL 中的白血病增殖细胞
DOI：
10.1186/s12967-017-1286-5
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发表时间：
2017-08-30
影响因子：
7.4
通讯作者：
Huang XJ
中科院分区：
文献类型：
--
作者：
Kong Y;Wu YL;Song Y;Shi MM;Cao XN;Zhao HY;Qin YZ;Lai YY;Jiang H;Jiang Q;Huang XJ
研究背景白血病增殖细胞（leukemia-promoting cells，LPC）的持续存在是Ph+ALL复发的主要原因之一。最近使用异种移植小鼠试验进行的研究确定，人Ph+ALL中的LPC富含CD 34 + CD 38 − CD 58 −组分。此外，一项队列研究表明，诊断时具有LPC表型的Ph+ALL患者的复发累积发生率显著高于具有其他细胞表型的患者，即使在同种异体移植前后接受了统一的基于伊马替尼的一线治疗，方法RNA测序（RNA-Seq）和实时定量聚合酶链反应（qRT-PCR）分析来自原发Ph+ALL患者的分选的LPC和其他细胞组分的基因表达谱。为了评估选择性BCR-ABL和/或Janus激酶（JAK）2抑制治疗（通过使用单药或ruxolitinib与伊马替尼或尼洛替尼联合治疗）对Ph+ALL LPC的影响，在体外以及体内使用亚致死照射和抗CD 122条件NOD/SCID异种移植小鼠试验研究了药物诱导的LPC凋亡。此外，从不同的受体小鼠组收获的骨髓细胞上进行western blot分析。结果RNA-Seq和qRT-PCR表明，JAK 2是更高的表达在分选的LPCs比在其他细胞组分在初发Ph+ALL患者。与选择性JAK 1/JAK 2抑制剂的组合治疗（ruxolitinib）和尼洛替尼通过在分子水平上降低磷酸化-CrKL和磷酸化-JAK 2活性，比单独或在体外和人源化Ph+ALL小鼠中的任一种疗法更有效地消除LPC。这项临床前研究为同时靶向BCR-ABL和JAK 2活性作为一种有前途的抗-原发性Ph+ALL患者的LPC治疗方法。
BackgroundAs one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34+CD38−CD58−fraction in human Ph+ALL. Additionally, a cohort study demonstrated that Ph+ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies.MethodsRNA sequencing (RNA-Seq) and real-time quantitative polymerase chain reaction (qRT-PCR) were performed to analyze the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL. In order to assess the effects of the selective BCR–ABL and/or Janus kinase (JAK)2 inhibition therapy by the treatment with single agents or a combination of ruxolitinib and imatinib or nilotinib on Ph+ALL LPCs, drug-induced apoptosis of LPCs was investigated in vitro, as well as in vivo using sublethally irradiated and anti-CD122-conditioned NOD/SCID xenograft mouse assay. Moreover, western blot analyses were performed on the bone marrow cells harvested from the different groups of recipient mice.ResultsRNA-Seq and qRT-PCR demonstrated that JAK2 was more highly expressed in the sorted LPCs than in the other cell fractions in de novo Ph+ALL patients. Combination treatment with a selective JAK1/JAK2 inhibitor (ruxolitinib) and nilotinib more effectively eliminated LPCs than either therapy alone or both in vitro and in humanized Ph+ALL mice by reducing phospho-CrKL and phospho-JAK2 activities at the molecular level.ConclusionsIn summary, this pre-clinical study provides a scientific rationale for simultaneously targeting BCR–ABL and JAK2 activities as a promising anti-LPCs therapeutic approach for patients with de novo Ph+ALL.
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影响因子：
28.5
作者：
Chen H;Liu KY;Xu LP;Liu DH;Chen YH;Zhao XY;Han W;Zhang XH;Wang Y;Zhang YY;Qin YZ;Liu YR;Huang XJ
通讯作者：
Huang XJ
影响因子：
20.3
作者：
Gallipoli, Paolo;Cook, Amy;Holyoake, Tessa L.
通讯作者：
Holyoake, Tessa L.
影响因子：
158.5
作者：
Kantarjian, Hagop;Giles, Francis;Ottmann, Oliver G.
通讯作者：
Ottmann, Oliver G.
影响因子：
11.4
作者：
Beillard, E;Pallisgaard, N;Gabert, J
通讯作者：
Gabert, J
影响因子：
20.3
作者：
Karjalainen, Riikka;Pemovska, Tea;Heckman, Caroline A.
通讯作者：
Heckman, Caroline A.