Title |
Ruxolitinib/nilotinib cotreatment inhibits leukemia-propagating cells in Philadelphia chromosome-positive ALL
|
---|---|
Published in |
Journal of Translational Medicine, August 2017
|
DOI | 10.1186/s12967-017-1286-5 |
Pubmed ID | |
Authors |
Yuan Kong, Yi-Lin Wu, Yang Song, Min-Min Shi, Xie-Na Cao, Hong-Yan Zhao, Ya-Zhen Qin, Yue-Yun Lai, Hao Jiang, Qian Jiang, Xiao-Jun Huang |
Abstract |
As 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. RNA 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. RNA-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. In 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 3 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 1 | 33% |
Science communicators (journalists, bloggers, editors) | 1 | 33% |
Members of the public | 1 | 33% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 28 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Master | 6 | 21% |
Researcher | 5 | 18% |
Student > Ph. D. Student | 4 | 14% |
Student > Bachelor | 3 | 11% |
Student > Doctoral Student | 3 | 11% |
Other | 2 | 7% |
Unknown | 5 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 6 | 21% |
Medicine and Dentistry | 6 | 21% |
Agricultural and Biological Sciences | 2 | 7% |
Psychology | 2 | 7% |
Immunology and Microbiology | 1 | 4% |
Other | 2 | 7% |
Unknown | 9 | 32% |